Immune-Neuro-Endocrine Interactions: Facts and Hypotheses

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Endocrin

e Review s

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6 b y Th e Endocrine SocietyVol. 17 , No. 1

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Immune-Neuro-Endocrin

e Interactions : Fact s and

Hypothese

s HUG O OSCA R BESEDOVSK

Y AND ADRIANA DEL REY

Division

of Immunophysiology, Institute of Physiology, Medical Faculty, Deutschhausstrafie 2, D-35037Marburg, Germany I . Introductio n II . Reciprocal Effects Between Immune and Neuro-Endo- crin e Mechanism s A . Receptor s fo r cytokines , hormones , neurotransmit - ters , and neuropeptides in immune, endocrine, and neura l cell s 1 . Receptor s fo r hormones , neurotransmitters , an d neuropeptide s i n immun e cell s2. Receptors for immune cytokines in endocrine gland s 3 . Receptors for immune cytokines in the nervous syste m B . Immune and neuro-endocrine products coexist in lymphoid , endocrine , an d neura l tissue s 1 . Neuro-endocrin e agent s i n lymphoi d organ s 2 . Immune cytokines in endocrine and nervous system s C . Hormones , neurotransmitters , an d neuropeptide s ca n affec t th e immun e syste m 1 . Endocrin e effect s o n th e immun e syste m 2 . Neural effects on the immune system 3 . Immune mechanisms that can be affected by neuro-endocrin e agent s D . Immun e cel l product s ca n affec t neuro-endocrin e mechanism s 1 . Effect s o f immune-derive d product s o n endo - crin e mechanism s2. Effects of immune-derived products on the ner- vou s syste m 3 . Metabolic effects of cytokines III . Immune-Neuro-Endocrine Circuits A . Lon g loop immune-neuro-endocrin e circuit s B . Immune-neuro-endocrine circuits operating at local level s C . Relevanc e o f immune-neuro-endocrin e circuit s fo r immunoregulatio n IV . Homeostati c an d Antihomeostati c Function s o f th e Im - mun e System : Contributio n t o Natura l Selectio n V . Outloo k A . Th e immun e syste m a s a diffuse , sensoria l recepto r orga n B . Is tha t all ?Address reprint requests to: Hugo O. Besedovsky, M. D., Division of

Immunophysiology

, Institut e o f Physiology, Medical Faculty,

Deutschhausstraj3

e 2 , D-35037 Marburg, Germany. Thi s wor k was supported by the Volkswagen Stiftung. I . Introductio n T H E existenc e o f mechanism s tha t provid e immunit y t o a n infectiv e agen t wa s inferre d fro m empirica l obser - vation s obtaine d throug h th e ingenuit y an d deductiv e ca - pacit y o f earl y investigators . Th e firs t procedure s fo r vacci - nation s an d serotherap y resulte d fro m thes e observations . Th e implementatio n o f thes e procedures , probabl y th e mos t importan t contributio n o f immunolog y t o medica l science ,was, at first, based on a very rudimentary knowledge of the immun e system . Durin g th e firs t hal f o f th e 20t h century , thi s rathe r primitiv e knowledg e coincide d wit h evidenc e show - in g tha t th e endocrin e an d nervou s system s integrat e an d regulat e differen t bodil y functions . Therefore , base d o n som e supportiv e data , i t wa s considere d tha t immun e mechanism s ma y als o b e influence d b y thes e systems . However , a t th e beginnin g o f th e secon d hal f o f th e 20t h century , mos t effort s wer e directe d a t understandin g th e molecula r an d cellula r basi s o f th e immun e respons e an d th e mechanism s o f ac - quisitio n o f immunologica l diversit y an d self-tolerance . Th e produc t o f thes e studie s i s formidable . A s a result , w e kno w th e structur e o f th e mai n molecule s (e.g. antibodies, T cell receptors ) tha t allo w recognitio n o f antigen s fro m insid e an d outsid e th e organism , a s wel l a s th e type s an d subtype s o f cell s tha t participat e i n a n immun e response . I n addition , th e molecula r an d geneti c basi s o f th e differentiatio n an d diver - sificatio n o f immunologica l cell s i s largel y understood . Fur - thermore , ou r knowledg e o f th e biochemica l an d molecula r basi s o f immun e cel l activatio n an d ho w thes e cell s interac t an d receiv e informatio n fro m antigen-presentin g cell s ha s bee n clarifie d t o a grea t extent . Th e existenc e o f autoregu - lator y mechanism s tha t ca n contro l th e immun e respons e ha s als o bee n established . I n contrast , muc h les s i s know n abou t ho w immunologica l cell s an d thei r product s interac t wit h othe r bodil y systems , an d abou t th e consequence s o f suc h interaction s fo r mechanism s intrinsi c an d extrinsi c t o th e immun e system . Thus , th e understandin g o f th e organizatio n o f th e immun e syste m itsel f ha s raise d essentia l question s concernin g it s physiologica l functionin g withi n th e whol e organism. Th e nee d to provid e answer s t o thes e question s i s becomin g increasingl y important , an d man y laboratorie s ar e no w focuse d o n understandin g th e functiona l an d molecula r basi s o f interaction s betwee n th e immun e syste m an d inte - grativ e neuro-endocrin e mechanisms . A s w e shal l discus s later , interaction s betwee n th e im - mune , endocrine , an d nervou s system s ar e necessaril y com - ple x sinc e eac h o f thes e system s i s intrinsicall y complex .64Downloaded from https://academic.oup.com/edrv/article/17/1/64/2548532 by guest on 16 August 2023 February, 1996IMMUNE-NEURO-ENDOCRINE INTERACTIONS65

Furthermore

, th e amoun t o f informatio n tha t i s no w avail - abl e i s enormous , and , i n som e instances , contradictor y o r ^ difficul t t o interpret . Therefore , thi s articl e wil l no t b e a n exhaustiv e revie w o f al l th e contribution s fro m th e multipl e laboratorie s engage d i n thi s fiel d o f research . Instead , i t wil l provid e a n analysi s o f th e availabl e informatio n withi n a define d conceptua l framework , which , eve n i f i t turn s ou t t o b e wron g i n certai n aspects , migh t serv e t o promot e furthe r . research . Th e mai n focu s o f thi s articl e wil l b e o n functiona l inter - action s betwee n immune , neural , an d endocrin e cell s an d thei r possibl e relevanc e t o physiologica l an d certai n patho - logica l processes . Thes e interaction s occu r a t s o man y level s tha t i t i s necessar y t o establis h som e prioritie s an d restric - tion s fo r th e followin g discussion . W e shall particularly high- * ligh t thos e studie s o f th e effect s o f th e product s o f immun e cell s o n neuro-endocrin e function s sinc e th e existenc e o f afferen t pathway s fro m th e immun e syste m t o mechanism s unde r centra l nervou s syste m (CNS ) contro l i s no w bein g intensivel y investigated . Certai n aspect s tha t wil l eithe r b e absen t o r onl y briefl y discusse d includ e psychosocia l influ - • ence s o n immunity , neuroimmunologica l brai n diseases , ef - fect s o f immun e cel l product s o n behavior , thermoregulatio n an d sleep , an d endocrin e disease s cause d b y th e immun e system . Molecula r an d subcellula r processe s underlyin g im - mune-neuro-endocrin e interaction s wil l no t b e discusse d i n detail , unles s i t i s necessar y fo r understandin g th e biologica l relevanc e o f suc h interactions . W e shall often refer to cytokines as immune-derived prod- * • ucts . However , a t present , th e ter m cytokin e i s widel y use d t o defin e polypeptidi c factor s release d b y practicall y an y typ e o f cells . More than 50 cytokines have been described and th e majorit y hav e been cloned. Most of them have pleiotropic effects , an d som e ac t togethe r synergisticall y o r ar e capabl e o f inducin g o r inhibitin g th e productio n o f othe r cytokines . » • Man y o f thes e factor s ar e produce d b y immunologica l cells . Th e immune-derive d cytokine s mentione d i n thi s revie w ar e thos e tha t ca n b e considere d a s mediator s o f immune-neuro - endocrin e interaction s becaus e the y exer t som e neuro-endo - crin e effec t o r thei r receptor s ar e presen t i n neuro-endocrin e tissues . Thes e cytokine s ar e liste d i n Tabl e 1 , togethe r wit h v thei r currentl y use d abbreviation . Thei r mai n immunologica l action s ar e als o briefl y summarized . II . Reciprocal Effects Between Immune and Neuro-

Endocrin

e Mechanism s A s schematicall y represente d i n Fig . 1 , th e evidenc e tha t immun e an d neuro-endocrin e mechanism s ca n affec t eac h othe r ha s bee n classifie d a s follows : A ) Immune , endocrine , o r neura l cell s ca n expres s receptor s fo r cytokines , hormones, neurotransmitters , an d neuropeptides ; B ) Immun e an d neuro-endocrin e product s coexis t i n lymphoid , endocrine , an d neura l tissue ; C ) Endocrin e an d neura l mediator s ca n affec t th e immun e system ; an d D ) Immun e mediator s ca n affec t endocrin e an d neura l structures .A. Receptors for cytokines, hormones, neurotransmitters, and neuropeptides in immune, endocrine, and neural cells

Reciproca

l expressio n o f receptor s fo r product s o f th e nervou s an d endocrin e system , a s wel l a s fo r th e immun e system , constitut e th e basi s o f immune-neuro-endocrin e interactions . Th e presenc e o f receptor s fo r hormones , neu - rotransmitters , an d neuropeptide s o n immunologica l cell s ha s bee n clearl y established , an d onl y a few classic works will b e mentione d below . However , mor e recen t studie s o n th e presenc e o f receptor s fo r immune-derive d messenger s o n endocrin e an d neura l cell s wil l b e reviewe d i n mor e detail .

1. Receptors for hormones, neurotransmitters, and neuropeptides

in immune cells. Immune cells can bind different hormones, neurotransmitters , an d neuropeptides . Fo r example , recep - tor s fo r corticosteroid s (1,2) , insulin (3,4), PRL (5,6), GH (7), estradio l (8) , testosteron e (9) , j3-adrenergi c agent s (10-14) , acetylcholin e (15,16) , endorphins (17), enkephalins (18), sub- stanc e P (SP) , somatostati n (SOM) , an d vasointestina l pep - tid e (VIP ) (19-21 ) hav e bee n demonstrate d i n lymphoi d o r accessor y cells . There is still some controversy regarding the presenc e o r th e numbe r o f certai n o f thes e receptor s o n im - munologica l cells . However , fo r th e purpos e o f thi s review , w e conside r i t mor e importan t t o discuss two aspects that are relevan t fo r th e fina l effec t o f neuro-endocrin e agent s o n immun e cells . First , receptors for neuro-endocrine ligands are not equally expresse d o n al l type s o f immun e cells . Fo r example , B lym- phocyte s expres s mor e j3-adrenergi c receptor s tha n T lym - phocytes , whil e CD8 + lymphocyte s (c y t o toxi c T cells ) ex - pres s fewe r receptor s tha n CD4 + cell s (helpe r T cells ) (13) . Thi s indicate s tha t signal s mediate d b y hormones , neuro - transmitters , an d neuropeptide s ca n preferentiall y target , an d therefor e influence , differen t type s o f immun e re - sponses . Second , th e numbe r o r th e activit y o f receptor s fo r a give n neuro-endocrin e agen t ma y chang e durin g th e acti - vatio n o f th e cell . For example, resting lymphocytes have no detectabl e receptor s fo r insulin , bu t the y appea r afte r stim - ulatio n wit h mitogen s o r allogenei c antigen s (3 , 4) . Afte r stimulatio n o f quiescen t cytotoxi c T lymphocyte s b y inter - leukin- 2 (IL-2) , ther e i s a n increas e i n j3-adrenergi c recepto r activit y (22) . The number of muscarinic receptors on human leukocyte s an d ra t T lymphocytes also increases when these cell s ar e activate d b y mitogen s an d allogenei c antigen s o r durin g ski n graf t rejectio n (23) . Thus , i t i s expecte d tha t signal s mediate d b y thes e hormone s o r neurotransmitter s wil l b e predominantl y perceive d b y cell s tha t hav e bee n activate d b y a n antigen . I n summary , th e presenc e o f receptor s fo r hormones , neu - rotransmitters , an d neuropeptide s o n immun e cell s i s a n absolut e requiremen t fo r neuro-endocrin e agent s t o exer t a n effect . However , a s clearl y establishe d fo r glucocorticoid s (24) , the magnitude of the effect of a given ligand does not necessaril y correlat e wit h th e numbe r o f receptor s presen t o n th e targe t cell . Thus, the identification of receptors should be take n onl y a s a n indicatio n tha t immun e cell s ca n perceiv e an d respon d t o messenger s presen t i n thei r natura l environ - ment . A s wil l b e discusse d later , severa l othe r factors , suc h a s th e differen t degre e o f sensitivit y o f th e variou s step s o fDownloaded from https://academic.oup.com/edrv/article/17/1/64/2548532 by guest on 16 August 2023

66BESEDOVSKY AND DEL REY

Vol. 17, No. 1

TABL E 1. Cytokines that can mediate immune-neuro-endocrine interactions

Abbreviatio

nNameMajor immune action IL-la , IL-1/ 3 IL-lr a IL- 2 IL-

3Interleukin-1 a; Interleukin-1/3

Interleukin-

1 recepto r antagonis t

Interleukin-

2

Interleukin-

3 IL- 4 IL- 6 IL- 8 IL-1 2 IFN 7 TNF a TGF/ 3 M-CS F G-CS F GM-CS F SC

FInterleukin-4

Interleukin-

6

Interleukin-

8

Interleukin-1

2

Interferon-

y Tumo r necrosi s factor- a

Transformin

g growt h factor-j 3

Macrophage-Colon

y stimulatin g facto r

Granulocyte-colon

y stimulatin g

Granulocyt

e an d macrophag e c o stimulatin g facto r Ste m cel l facto

rDifferentiation and function of cells involved ininflammatory and immune responses; T T helper cellsto produce and secret IL-2 and the expression of IL-2receptors; f B cell proliferation and production of Ig, f

proliferatio n an d activatio n o f N K cell s I IL- 1 activitie s 1 T cel l proliferatio n an d differentiation , f N K activity , promote s proliferatio n o f B cells and Ig secretio n synergize s wit h specifi c factor s t o stimulat e productio n an d differentiatio n o f macrophage s (an d othe r bloo d cells )

Induce

s differentiatio n int o T helpe r cells , proliferatio n an d differentiatio n o f B cells, diverse effects on T cells an d monocyte s

Induce

s growt h an d differentiatio n o f T cell s an d B cells ,activates hematopoietic progenitor cells

Induce

s chemotacti c activit y fo r T cell s . Induces differentiation of T helper cells, f growth and activit y o f T an d N K cell s I Macrophag e activity , regulate s specifi c immun e response s Wid e immunologica l effect s throug h inductio n o f othe r growt h factor s an d cytokines ; immunostimulan t an d mediato r o f inflammator y respons e i Growt h o f man y cells , N K activit y an d T an d B cel lproliferation; with IL-4 f IgA secretion I Variou s function s o f monocyte s an d macrophages , promote s growt h an d developmen t o f macrophag e colonie s I Productio n o f neutrophi l an d macrophag e colonie s

Promote

s growt h an d differentiatio n o f multipotentia l progenito r cells , f al l cell s i n th e granulocyte , macrophag e an d eosinophi l lineag e

Synergize

s wit h variou s growt h factor s t o f myeloid , erythroi d an d lymphoi d progenitor s Th e cytokine s liste d abov e ar e produced , althoug h no t exclusively , b y immunologica l cells . Onl y thos e that , a t present , ca n b e considere d a s mediator s o f immune-neuro-endocrin e interaction s becaus e the y exer t som e neuro-endocrin e effec t o r thei r receptor s ar e presen t i n neuro-endocrin e tissues , ar e included . NK , Natura l kille r cells ; Ig , immunoglobulins ; f » stimulate; |, inhibit. a n immun e respons e an d th e presenc e o f othe r agents , wil l influenc e th e fina l effec t o f a give n ligand . 2 . Receptors for immune cytokines in endocrine glands. Comple- mentar y t o th e studie s mentione d abov e i s th e identificatio n o f receptor s fo r immune-derive d product s i n endocrin e glands . Thes e studie s are , i n general , mor e recen t tha n thos e mentione d i n th e previou s section . Althoug h valuabl e evi - denc e showin g th e existenc e o f receptor s fo r cytokine s o n endocrin e tissu e ha s bee n obtaine d fro m norma l an d tumo r cel l lines , w e hav e chose n studie s usin g norma l tissue s t o illustrat e thi s point . A summar y o f severa l o f th e report s availabl e i s given in Table 2, where receptors for interleukins o n th e pituitary , adrenal , thyroid , pancreas , testis , an d ovar y ar e mentione d wit h th e correspondin g bibliographi c refer - enc e (25-39) . Th e tabl e doe s no t indicat e whethe r th e meth - odolog y use d i n a give n repor t ha s resulte d i n th e charac - terizatio n o f a recepto r o r o n th e identificatio n o f a specifi c bindin g site .As can b e seen in Table 2, most reports deal with receptors fo r IL-1 . As a whole, receptors for IL-la and j3, or the cor- respondin g messenge r RN A (mRNA) , hav e bee n identifie d i n ra t an d mous e pituitary , mainl y locate d i n th e adenohy - pophysis . Receptor s o r bindin g site s fo r IL- 6 an d IL- 2 hav e als o bee n foun d i n th e pituitary . IL-

1 receptors have not been

foun d i n th e adrenal s (28 , 40), although a recent report sug- gest s tha t the y migh t b e present in bovine adrenal medullary cell s (41) . There are a few reports showing that IL-1 receptors, o r th e correspondin g mRNA , ar e als o presen t o n thyroi d cells , in the endocrine pancreas, and in certain regions or specifi c cell s o f th e ovar y an d o f th e testis . 3 . Receptors for immune cytokines in the nervous system. After the findin g tha t exogenou s administratio n o f certai n cytokine s coul d induc e pronounce d endocrin e change s know n t o b e unde r neura l contro l (fo r reference s se e Section D), a large numbe r o f report s becam e availabl e showin g tha t receptor s fo r som e o f thes e cytokine s can , i n fact , b e demonstrate d i nDownloaded from https://academic.oup.com/edrv/article/17/1/64/2548532 by guest on 16 August 2023 February, 1996IMMUNE-NEURO-ENDOCRINE INTERACTIONS67 Immun e an d neuro-endocrln e mechanism s ca n affec t eac h othe r FIG

. 1. Schematic representation of how im-mune and neuro-endocrine mechanisms can af-fect each other: A, Immune, endocrine, or neuralcells can express receptors for cytokines, hor-mones, neurotransmitters, and neuropeptides. B,Immune and neuro-endocrine products coexist inlymphoid, endocrine, and neural tissue. C, Effectsof neuro-endocrine agents on immune mecha-nisms. D, Effects of immune-derived products onneuro-endocrine mechanisms. CY, cytokine; H,hormone; NT, neurotransmitter; NP, neuropep-

tide . C . EFFECT S O F NEURO-€NDOCRIN E AGENT S tntarmadiat a matabolls m Signa l trantductlo n

Selectio

n

Radrculatio

n

Traffi

c

Cytokln*

* Cal l interaction s

Anllga

n praaantatlo n

Effacto

r ntachaniBin s

Autoragulator

y procatM a

Naurotranamilla

r

Nauropaplid

e Immun o orgon/llaau o 1CY H NTN P

Endocrin

e glan d 0 . EFFECT S O F IMMUNE-DERIVE D PRODUCT S

Endocrin

a Glan d

Naurotrantmlllar

a

Nauropapllda

a

Naurona

l activit y

Naurona

l growth , diftarantlatlo n an d rapai r

Thannoragutatlo

n Foo d inlak a Slaa p

Bahavlo

r th e CNS. Different techniques such as autoradiography, im- munoautoradiography , in situ histochemistry , an d in situ hybridizatio n histochemistr y (a t time s combine d wit h re - vers e transcriptase-polymeras e chai n reaction) , hav e bee n used . A s a whole , th e existin g evidenc e indicate s th e pres - enc e in the brain of receptors, or of the corresponding mRNA, fo r IL- 1 a an d j3 , IL-2 , IL-4 , IL-6 , tumo r necrosi s factor- a (TNFa) , interferon- y (IFNy) , macrophage-colon y stimulat - in g facto r (M-CSF) , an d ste m cel l facto r (SCF) , eithe r unde r basa l condition s o r afte r inductio n (25 , 26
, 28
, 32
, 42-62)
.

Probabl

y th e mos t studie d receptor s ar e thos e fo r IL-1 .

Althoug

h no t al l studie s completel y agre e o n th e localizatio n o f thes e receptor s i n th e brain , ther e i s a genera l consensu s that , i n adul t mic e an d rats , IL- 1 receptor s ar e mainl y con - centrate d i n th e dentat e gyru s o f th e hippocampus . Som e author s hav e foun d tha t thes e receptor s ar e presen t consti - tutively , whil e other s hav e detecte d the m afte r endotoxi n administration . Mor e recently , th e proble m o f th e modula - tio n o f IL-

1 receptors in the brain by glucocorticoids or adre-

nalectom y ha s bee n addressed . Tabl e 3 summarizes most of th e studie s tha t hav e reporte d th e presenc e o f receptor s fo rdifferent cytokines in brain tissue . Studies on the presence of receptor s o n isolate d brai n cell s hav e no t bee n included .

B. Immune and neuro-endocrine products coexist in

lymphoid, endocrine, and neural tissues

Clearly

, fo r exertin g reciproca l immune-neuro-endocrin e effects , hormones , neurotransmitters , an d neuropeptide s mus t reac h immun e cells , an d conversely , neuro-endocrin e structure s nee d t o becom e expose d t o product s o f activate d immun e cells .

1. Neuro-endocrine agents in lymphoid organs. In their physio-

logica l environment , immunologica l cell s ar e expose d t o agent s extrinsi c t o th e immun e syste m suc h a s hormones , neurotransmitters , an d neuropeptides . I n additio n t o bein g expose d t o hormones , immunologica l organ s ar e innervate d (63-65) . For example, peri vascular plexuses within the spleni c whit e pul p sen d singl e noradrenergi c fiber s betwee n surroundin g lymphocytes , an d som e o f thes e nerve s com e i n ver y clos e contac t wit h immunologica l cell s (65 , 66)
. Also ,Downloaded from https://academic.oup.com/edrv/article/17/1/64/2548532 by guest on 16 August 2023

68BESEDOVSKY AND DEL REYVol. 17, No. 1

TABL

E 2. Receptors for cytokines in endocrine glands

Recepto

r for" IL-l o IL- 1 a an d /

3IL-1 (I)

IL- 1 (I ) IL- 1 (I ) IL- 1 (II) f t IL-1/ 3 IL-l aIL-1 (I) 6 IL- 1 (I) 6 IL- 1 (I ) IL- 1 (I ) IL- 1 (I) 6 IL- 2 (a-chain ) IL- 2 IL- 2 IL- 6

Endocrin

e tissue/gland

Pituitar

y

Pituitar

yAnterior pituitary

Anterio

r pituitar yAnterior pituitaryAnterior pituitaryThyroid

Thyroid

0

Endocrin

e pancrea s

Ovary*

*Ovary 6 Testi /Testis^

Pituitar

y

Anterio

r pituitary' 1

Exocrin

e pancrea s

Anterio

r pituitar y

Specie

s Ra t Mous eMouse Mous eMouseMouse Pi g Huma nMouse Huma nMouseMouseMouse Mous e Ra t Ra t Ra t

Referenc

e 2 5 2 627
2

8292930

3 132
3 334
2 735
3 6 3 7 3 8 3 9 ° A s use d here , doe s no t distinguis h recepto r fro m bindin g site . 6 Indicate s detectio n o f transcript s fo r correspondin g receptor ; (I) , (II ) indicate s recepto r type . c Secondar y cultures . d Transcript s foun d i n whol e ovarie s an d follicula r aspirates . e I n theca-interstitia l laye r o f growin g follicles , cytoplasm a an d plasm a membran e o f oocyte , in granulosa cells, in granulosa-luteal cell s o f th e corpu s luteum . ^I n epididymi s an d interstitia l are a o f th e testis . 8 I n interstitia l cells , cytoplas m o f th e epitheliu m o f epididyma l ducts . h IL- 2 receptor s ar e colocalize d wit h ACTH-positiv e cells . fiber s fro m primar y sensor y neuron s ca n contac t accessor y cell s an d probabl y T cell s a t site s o f inflammatio n an d else - wher e (67) . Immun e cell s ca n b e expose d t o hormone s an d neuropep - tide s produce d b y immun e cell s themselves . Ther e i s evi - denc e tha t POMC-derive d peptides , such as ACTH and /3-en- dorphins , ca n b e produced by immunological cells. This was firs t demonstrate d b y th e detectio n o f ACTH-lik e immuno - reactivit y i n leukocyte s (68) . However, it is still controversial whethe r thi s peptid e i s identical to ACTH of pituitary origin, whethe r i t i s inducible by CRH, and whether it is released (69, 70)
. It has been reported that lymphocyte-derived ACTH is insufficien t t o stimulat e th e adrena l glan d i n hypophysec - tomize d mic e (71 ) and rats (72). This is in agreement with the findin g tha t it s productio n i s ver y lo w (72 ) an d restricte d t o certai n subpopulation s o f immun e cell s (73) . G H an d PR L hav e als o bee n reporte d t o b e produce d b y immun e cell s (74 , 75)
. As we shall discuss later, hypophysectomy results in a profoun d immunodeficiency . Thus , pituitary-lik e hormone s o f immun e cel l origi n ar e no t enoug h t o compensat e fo r th e effect s tha t pituitary-derive d hormone s exer t o n immun e cells . The fact that these lymphocyte-derived peptides are produce d b y distinc t subpopulation s o f immun e cell s (70,73) suggest s tha t the y ma y pla y a rol e i n immunoregulatio n b y exertin g paracrine/autocrin e actions . Th e sam e consider - ation s ma y appl y t o neuropeptide s suc h a s VI P (76 ) an d S P (77) tha t ar e produce d b y eosinophil s an d mas t cells , i n additio n t o bein g presen t i n th e innervatio n o f immun e tissues . 2 . Immune cytokines in endocrine and nervous systems.a. Cytokines in the endocrine system. Immune-derived prod- uct s ma y influenc e endocrin e structure s a s humora l signals .

However

, i t ha s als o bee n foun d tha t som e cytokines , eithe r constitutivel y o r afte r induction , ar e presen t i n endocrin e glands . Probabl y th e bes t studie d cytokin e i n thi s respec t i s IL-6 . Mouse or rat anterior pituitary cells secrete IL-6 spon- taneousl y (78-81) . Increased production is induced, either in vivo o r in vitro, by lipopolysaccharide (LPS) (80-86), phorbol myristat e acetat e (81) , IL-1/ 3 (79 , 82
, 87
, 88)
, TN F (87 , 89)
, pituitar y adenylat e cyclas e activatin g polypeptid e (90) , cal - citoni n gene-relate d peptid e (90) , IFN y (87) , an d prostag - landi n E 2 (82) . cAMP-dependen t (90 ) an d -independen t (82 , 90
) signa l transductio n pathway s see m t o b e involve d i n thes e effects . IL- 6 releas e i s inhibite d b y glucocorticoid s (82 , 84
, 91, 92). As determined by Northern blot analysis, the predominan t for m o f IL-

6 mRNA found in the pituitary after

eithe r intraperitonea l o r intracerebroventricula r administra - tio n o f LP S seem s t o b e different from that found in the spleen unde r th e sam e circumstance s (86) . The presence of folliculo- stellat e cell s i s essentia l fo r IL- 6 productio n (78) . Som e au - thor s hav e show n that , basally , th e anterio r an d posterio r pituitarie s releas e large r amount s o f bioactiv e IL- 6 tha n th e media l basa l hypothalamu s o r th e parieta l cortex , but that the inductio n o f th e releas e o f thi s cytokin e b y endotoxi n occur s onl y i n th e anterio r pituitar y an d hypothalamu s (80) . Othe r author s hav e reporte d tha t mos t o f th e IL-6-containin g cell s fro m freshl y isolate d mous e pituitar y ar e positiv e fo r S-100 . I n contrast , neithe r immunoreactiv e no r bioactiv e IL- 6 wa s foun d i n AtT-2 0 cell s (93) . Recently , i t wa s foun d tha t cell s fro m th e neurointermediat e pituitar y lob e ca n als o secret e IL-6 , and that LPS and IL-1/3 stimulate its release and the accumulatio n o f IL- 6 mRN A i n thes e cell s (94) . Vasopressi n an d oxytoci n inhibi t th e releas e o f IL-

6 induced by IL-1/3 and

LP S fro m cell s o f th e neurointermediat e lob e withou t affect - in g it s releas e fro m anterio r pituitar y cell s (94) .

Immunoreactiv

e IL-1/ 3 ha s bee n localize d i n th e cyto - plasmi c granule s i n anterio r pituitar y endocrin e cell s an d colocalize d wit h TS H i n thyrotropes . LP S induce s a marke d increas e i n anterio r pituitar y IL-1/ 3 messag e (95) . Also , constitutive expression of TNFa mRNA and its in- ductio n b y periphera l injectio n o f LP S wa s demonstrate d i n th e pituitar y (96) . A n IL-8-lik e neutrophi l chemoattrac - tan t i s als o foun d i n ra t norma l anterio r pituitar y gland , an d i t ca n b e furthe r induce d b y TNF a i n a dose-dependen t manne r (97) .

Regardin

g th e presenc e o r induce d expressio n o f cyto - kine s i n th e adrena l gland , IL-1-lik e immunoreactivit y wa s demonstrate d i n noradrenergi c chromaffi n cell s (98) . Since thes e cell s ar e o f neurona l type , thes e result s ar e discusse d i n th e followin g section . IL- 6 i s produce d b y adrena l zon a glomerulos a cells ; its release is stimulated by several secre- tagogues , includin g IL-l a an d /3 , angiotensin II, and ACTH (99) . The maximal release from zona glomerulosa cells is mor e tha n 10-fol d greate r tha n tha t fro m zon a fasciculata / reticulari s cells . Dexamethasone , a n inhibito r o f IL- 6 pro - ductio n i n severa l tissues , ha s n o effec t o n eithe r basa l o r stimulate d IL- 6 productio n i n th e adrena l (99) . Measurable level s o f TNF a wer e foun d i n abou t 50
% o f huma n feta l adrenals , bu t i n non e o f th e adul t adrenal s studie d (100) . W e hav e no t bee n abl e t o fin d report s o n th e presenc e o fDownloaded from https://academic.oup.com/edrv/article/17/1/64/2548532 by guest on 16 August 2023 February, 1996IMMUNE-NEURO-ENDOCRINE INTERACTIONS69 TABL

E 3. Receptors for cytokines in the brain

Recepto

r for"SpeciesLocalizationModulationRef. IL- 1 IL-

1IL-1/3IL-laIL-la and /3

IL-1 6 IL- 1 (I) 6 IL- 1 (I) 6 Ra t Ra tMouseMouse Mous e Mous e Mous e IL-1/ 3 IL-

1IL-1 (I)

6 IL- 1IL-1 IL- 1 (I , II )and 6 IL- 2 IL- 2 IL- 4IL-6 IL-6 6 IL-6 6 IL-6 6 IL-6 6 Mous eMouseMouseMouse Huma i Ra t Ra t Mous e Bovin e Ra t Ra t Ra t Ra tRat Widespread, specially dense areas: dentate gyrus (granule cell layer), pyramida l cel l laye r o f Hip ; granule cell layer of Cer, HyAlmost all neuronsHy, Cx

Discret

e area sHigh concentration: dentate gyrus (granule cells), choroid plexus meninges ; low concentrations: Cx

Intens

e signal : dentat e gyru s (granul e cells ) wea k t o moderat e signal : pyramida l cel l laye r o f th e hilus , CA 3 regio nDentate gyrus

Intens

e signal : dentat e gyru s (granul e cel l layer) , midlin e raph e system

,choroid plexus, endothelial cells of postcapillary venules weak tomoderate signal: pyramidal cell layer of hilus and CA3 region of Hip,anterodorsal thalamic nucleus, Purkinje cells of cerebellar Cx, scatteredclusters over the median eminenceHy, Hip

Dentat

e gyrus , choroi d plexu sBHip (dentate gyrus) neurons of Hip Norma l astrocytes , norma l brai n tissu e TNF a TNF a p7 5 TN F p5 5 TN F IFN 7 M-CSF 6 M-CS F an d 6 SC F an d 6 Hi p Hip , molecular layer of CxB H

yCA1-CA4 regions, dentate gyrus of Hip habenulae, dorsomedial andventromedial Hy, internal capsule, optic tract and piriform CxHy

Highes

t level s i n Hi pPyramidal neurons, granular neurons of Hip , neurons of habenular nucleus , dorsomedia l an d ventromedia l Hy , i n pirifor m Cx , i n scattere dneurons of Cx in granular cells of Cer, in medial preoptic nucleus and latera l ventricl e Mous e Greates t i n BS , les s i n Cer , als o detecte d i n Cx , Th l an d basa l gangli a Mous e Wea k binding , entir e B Huma n Norma l astrocytes , norma l brai n tissu e Huma n Norma l astrocytes , norma l brai n tissu e Mous e B Huma n Norma l astrocytes , norma l brai n tissu e Huma n Norma l astrocytes , norma l brai n tissu e 4 2 4 3 4 4 2 5 2 6 4 5 3 2 2 8 c d e f 8 h 4 647
4 849
5 051
5 2 5 3 5 455
5 6 5 7 5 8 5 9 6 0 6 1 5 1 5 1 6 2 5 1 5 1 Hy , hypothalamus ; Hip , hippocampus ; Cer , cerebellum ; Cx , Cortex ; BS , brai n stem ; Thl , thalamus ; B , brai n (regio n no t specified) . a A s use d here , doe s no t distinguis h recepto r fro m bindin g site . 6 Indicate s detectio n o f mRN A fo r correspondin g receptor ; (I) , (II ) indicate s recepto r type . c Expressio n influence d followin g tw o injection s o f LPS . d Modulate d b y LPS , effec t o f macrophag e depletion . c Modulate d b y LPS . ^Effect s o f LPS , glucocorticoid s an d adrenalectomy . * Differentia l expressio n durin g postnata l development . h Differen t expressio n pattern s durin g development . 1 Studie d durin g development . cytokine s o n th e thyroi d unde r condition s tha t do not involve autoimmun e processe s affectin g thi s gland . I n th e pancreas , i t ha s bee n show n tha t isle t cell s fro m norma l mic e ca n expres s TNF a mRN A i f culture d i n th e presenc e o f IL-1/ 3 (101) . I n th e gonads , i t ha s bee n foun d tha t th e testi s contain s larg e amount s o f IL- 1 (102) . IL- 1 bioactivit y wa s foun d i n testicula r interstitia l flui d an d cytosoli c preparation s (103 , 104)
. It has been shown that the cytokine is produced by

Sertol

i cell s (105,106 ) an d tha t in vivo treatment of rats with LH s an d C G induce s IL-1/

3 mRNA accumulation in purifiedLeydig cells (107). Small quantities of bioactive TNFa were

detecte d i n conditione d mediu m fro m roun d spermati d frac - tions , and TNF mRNA is found in both pachytene spermato- cyt e an d roun d spermati d fraction s wher e i t wa s als o de - tecte d b y in situ hybridization (108). The production of TNFa bioactivit y b y testicula r macrophage s ha s bee n demon - strated , whil e mediu m fro m culture d Sertol i cells , Leydi g cells , and peritubular cells appear devoid of such activity (109) . However, the bioactivity observed by assaying testic- ula r interstitia l flui d obtaine d in vivo could not be neutralized b y antibodie s t o TN F (110) . In

vitro, it seems that the mainDownloaded from https://academic.oup.com/edrv/article/17/1/64/2548532 by guest on 16 August 2023

70BESEDOVSKY AND DEL REYVol. 17, No. 1

sourc e o f LPS-induce d TNF a i s testicula r interstitia l macro - phage s (111) . Whil e som e author s hav e no t foun d IL-1-lik e bioactivity in th e ovar y (102) , others have reported that, after LPS injection int o mice , mRN A fo r IL-l a an d j

3 is found in the ovary and

uteru s (112) . Afte r pharmacologica l inductio n o f follicula r maturatio n an d ovulation , an d formatio n o f th e corpu s lu - teu m in vivo, it was found that IL-lj3 mRNA is localized in thec a interstitia l cell s (113). In patients pretreated with GnRH analogs , IL-

1 bioactivity was found in granulosa and cumu-

lu s cel l culture s an d i n follicula r flui d (114) , an d mRN A wa s detecte d i n preovulator y follicula r aspirate s (33) . Interest - ingly , i t wa s foun d tha t IL-

1 in human ovarian cells and in

periphera l bloo d monocyte s increase s durin g th e lutea l phas e (115) . In the mouse, IL-la and /3 immunoreactivity was foun d t o b e confined to the theca-interstitial layer of growing follicle s an d durin g ovulation , whil e durin g luteinization , granulosa-lutea l cell s o f th e corpu s luteu m demonstrate d stron g stainin g (34) . Culture d huma n ovaria n surfac e epi - theliu m secret e bioactiv e IL-1 , IL-6, CSF-1, G-CSF, and some

GM-CSF

, whil e n o IL-2 , IL-3 , or IL-4 was detected (116). By in situ hybridization, transient expression of IL-6 mRNA was demonstrate d i n gonadotropin-prime d hyperstimulate d ovaries , wit h maxima l mRN A level s coincidin g wit h th e perio d o f formatio n o f a capillar y networ k aroun d follicle s (117) . Other authors have shown that the rat ovary produces IL-6 , GM-CSF, TNFa, and IL-1 before and during the ovu- lator y proces s (118) . Immunoreactive TNFa was observed in granulos a cell s o f health y antra l an d atreti c follicle s an d appeare d t o b e secrete d b y th e granulos a cell s (119) . Immu - noreactiv e an d bioactiv e TNF a i s presen t i n th e follicula r flui d o f wome n undergoin g GnR H an d C G treatmen t t o stimulat e thei r sexua l cycle s (120) . TNF a mRN A wa s de - tecte d i n ra t ovar y (121) . I n th e mouse , TNF a mRN A an d protei n wa s observe d i n oocyte s o f health y follicle s (122) . b. Cytokines in the nervous system.

Cytokines

in the brain: Astrocytes and microglial cells were th e brai n cell s tha t wer e firs t show n t o produc e severa l cy - tokine s (123 ; fo r revie w se e Ref . 124)
. Mor e recently , i t ha s bee n reporte d tha t certai n neuron s ca n als o produc e cyto - kine s suc h a s IL-

1 (see below). We have chosen here to review

briefl y thos e studie s tha t dea l no t wit h in vitro production of cytokine s b y isolate d neura l cells , bu t rathe r thos e investi - gatin g thei r presenc e o r inductio n i n nervou s tissue . Th e summar y tha t follow s als o doe s no t includ e an y detaile d discussio n o f th e inductio n o f cytokine s durin g encephalo - pathies , suc h a s thos e cause d b y brai n infections . Althoug h suc h studie s are , o f course , vita l fo r understandin g th e im - portanc e o f cytokine s fo r brai n pathophysiology , i t i s usually difficul t t o determin e whether , unde r thes e circumstances , cytokine s i n th e brai n ar e produce d b y residen t cell s o r ar e derive d fro m invadin g periphera l immunocompeten t cells .

Furthermore

, i n mos t cases , i t i s no t clea r whethe r locall y induce d immun e cytokine s contribut e t o th e regulation of the immun e respons e i n th e CN S b y affectin g neura l mecha - nisms . Mos t o f th e report s o n th e presenc e o f cytokine s i n th e nervou s syste m refe r t o th e brai n (46,52,53,57,58,62,83,84 , 96
, 125-162). Table 4 attempts to summarize these reports.

Severa

l cytokines , suc h a s IL-1 , its natural receptor antago-nist, IL-2, IL-3 , IL-6, IL-8, IL-12, and IFN7 have been found t o b e constitutivel y presen t i n th e CNS . The results are more controversia l regardin g th e constitutiv e expressio n o f TNFa .

Moreover

, althoug h al l report s agre e tha t LP

S administration

result s i n furthe r expressio n o f IL- 1 i n th e brain , no t al l o f the m indicat e tha t i t occur s i n th e sam e region . A t leas t par t o f thes e discrepancie s coul d b e explaine d b y th e divers e methodolog y used , whic h range s fro m immunocytochemis - tr y o r in situ hybridizatio n t o measurement s o f cytokin e bioactivit y o r concentration , o r expressio n o f th e correspond- in g mRNA , and/o r b y th e differen t sensitivit y o f th e meth - ods . Furthermore, in reports dealing with cytokine induction i n th e brain , th e dose s o f LP S administere d ar e rathe r high . Thi s i s particularl y relevan t becaus e thi s cytokin e induce r ca n distur b th e blood-brai n barrie r (163) . I n addition , th e possibl e contributio n o f endothelia l cell s o r o f th e bloo d a s ^ sourc e o f cytokine s i n th e brai n ha s i n genera l no t bee n excluded . I n summary , certai n cytokines , eithe r constitutivel y o r af - te r induction , ar e presen t i n th e brain . Th e precis e localiza - tio n o r compartmentalizatio n o f thes e cytokines , an d whethe r mor e physiologica l stimul i tha n thos e use d s o fa r 4 resul t i n thei r increase d centra l production , nee d stil l t o b e clarified .

Cytokines

in the peripheral nervous system: Regarding the presenc e o f cytokine s i n periphera l neura l tissue , i t ha s bee n reporte d tha t IFN7-lik e immunoreactivit y i s present in nerve terminal-lik e profile s i n spina l cor d an d i n a subpopulatio n o f primar y sensor y ganglio n cell s (159) . Suc h immunoreac - tivit y wa s als o foun d i n smal l sensor y neuron s i n dorsa l roo t gangli a an d i n postsynapti c neuron s o f th e sympatheti c an d parasympatheti c nervou s syste m (164) . However, it was later conclude d tha t th e neurona l IFNy-lik e immunoreactiv e ma - teria l i s clearly distinct from lymphocyte-derived IFN7 (165).

IL-1-lik

e immunoreactivit y wa s demonstrate d i n nora - drenergi c chromaffi n cell s o f ra t an d mous e adrena l glan d (98) . This IL-1 was shown to be biologically active. Reserpine, * whic h i s know n t o deplet e catecholamines , cause d releas e o f th e IL-1-lik e immunoreactiv e materia l (98). mRNA content of IL-l a i n th e adrena l glan d i s increase d b y systemi c admin - istratio n o f cholinergi c agonists , bu t th e level s o f IL-l a pro - tei n ar e reduced . LP S i s able to induce the expression of IL-la mRN A an d protei n i n th e adrena l glan d (166) . Immunore - activ e IL- 1 an d IL- 1 mRN A hav e bee n foun d i n culture d sympatheti c gangli a (167) . C. Hormones, neurotransmitters, and neuropeptides can affect the immune system A

Studie

s concernin g neuro-endocrin e effect s o n immun e function s wer e performe d a s earl y a s a t th e beginnin g o f thi s century . Thus , a comprehensiv e revie w o f th e availabl e in - formatio n i s impossibl e here . Therefore , w e shal l provid e onl y a genera l overvie w an d som e example s fro m ou r ow n laboratory . However , t o provid e a n understandin g o f th e contributio n o f hormones , neurotransmitters, and neuropep- ~i tide s t o immunoregulation, we will provide a more thorough discussio n o n th e level s a t whic h a n immun e respons e coul d b e unde r neuro-endocrin e control .Downloaded from https://academic.oup.com/edrv/article/17/1/64/2548532 by guest on 16 August 2023 February, 1996IMMUNE-NEURO-ENDOCRINE INTERACTIONS71 TABL E 4. Constitutive or induced expression of cytokines in the brain

Cytokin

e IL-1/ 3 IL-1/ 3 IL-1/ 3 IL-1/ 3 IL-1/

3IL-1/3

IL-1/ 3 IL-1/ 3 IL-1/ 3 IL-1/ 3 IL- 1 IL-1/

3IL-1/3

IL-1/

3IL-1/3IL-1/3IL-laIL-la

IL-1/

3IL-la, /3IL-1/3

IL-

1IL-1/3

IL-lr a IL- 2IL-2 IL- 3 IL- 6 IL- 6 IL- 6IL-6 IL-

6IL-6IL-6

IL- 6 IL-

8IL-12

(p35 ) TNF aTNFaTNFa TNF aTNFa TNF a TNF a TNF a TNF a TNF a TNF a IFN y

Specie

s Ra t Ra t Ra t Ra t Ra tRat Ra t Ra t Ra t Ra t Ra t Ra tRat Ra tMouseMouseMouseMouse Rabbi tRabbit Pi gCatHuman Ra t Ra tRat Mous e Ra t Ra t Ra tRat Ra tRatRat Mous e Ra tMouse Ra t Ra t Ra t Ra t Mous e Mous e Mous e Mous e

Chicke

n Pi g

Guinea-pi

g Ra t Regio n

Granul

e cell s dentat e gyru s pyramida l cell s Hip , granul e cell s Ce rgranule/periglomerular cells, olfactor y bulb , disperse d cell sVMH; FCxCx, Thl, Hy, Hip

Periventricula

r media l Hy , Hi pand olfactory tubercle H yForebrainHyB

Meninges

, choroi d plexu s brai nblood vessels, non-neuronalcells in parenchyma Cx , Hip , Str , Th lHy BS , diencephalon (extracellular)

Severa

l region sCx, Thl, Hip H yStr, Thl Hip , HyHipStr, Thl, Cx, Hip OVL

TBHip and blood vessels

CS F fro m thir d ventricl e H y PVN , Hip , Ce r Hip , Str, CxMedian eminence

Arcuat

e nucleu s Hip , Cx, septum

Discret

e area s Ce r CS F Hip , Hy, Cer H yAnterior Hy Hip , Str, Cer, neocortexFacial nucleusCx, Hip, Thl, Hy B PVN , Hi pB CS F Cx , Hip , Hy , St r CS F H yStr, Thl, Cx, Hip B

Neuron

s o f H yBed nucleus stria terminalis, incaudal raphe nuclei, along ventra l pontin e an d medullar y surfac e B , neural tube, peripheral mixe d spina l nerve sBrain neuroepithelium Purkinje neuron s Ce rChoroid plexus

Ependyma

l cell s

Network

s o f nerv e terminal-lik e profile s

Detecte

d by

Bioassay

, IS H

Norther

n IH C

Norther

n ISH ; RT-PC

RNorthern

Bioassa

y IH C

Norther

n EIM A

Bioassa

y IS

HRT-PCR

IRM

APCRELISAPCRIHC

IH

CRIAIHC

Bioassa

yIHC ISH , H C IH CIAR

IHC/Norther

n

Bioassa

y ISH , Norther n RT-PC

RBioassay

RT-PC

RISHRT-PCR

Norther

n ISH , Norther nNorthern

Bioassa

y RT-PC

RBioassay

PC RIHC

Norther

n

Wester

n

Wester

n

Wester

n IHC , ISH IHC , ISH IH C C/ I c / /I : convulsants C / /I : methamphetamineC/I: LPS-IFN /I : immobilization stress

Transient

, durin g ontogen y /I : endotoxin /I : transient ischemia /I : endotoxin /I : LPS icv, ip C/I : f kaini c aci d /I : f kainic acid C/I : t LP SC(-)/I: LPSC/I: 2 x LPSC(-)/I: LPSC(-)/I: hippocampal lesion /I : endotoxin /I : LPSC/

C(-)/I

: endotoxi n ic vC/ C / c /c/ c / /I : LPS C / n o inductio n b y LP S C / /I : LPS through IL-1 Durin g developmen t /I : axotomy facial nerve /I : kainic acid Durin g developmen t C /C/ /I : LPS icv /I : kainic acidC(-)/I: LPS icv, aged rats C/I : LP S

C(-)/I

: hippocampa l lesio n durin g developmen t a Durin g developmen t Durin g developmen t /I : LPS /I : LPS C / Ref . 12 5 12 6 12 7 12 8 12 9130
13 1 13 2 13 3 13 4 13 5 13 6137
13

813946139140

14

1142143

14 4145
14 6 5 253
14 7 14 8 83,8
4 5 7149
5

8150137151

15 2153
15 4 13 7 15 5 9 6140
15 1 15 6 15 7 15 7 15 8 15 8 15

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72BESEDOVSKY AND DEL REYVol. 17, No. 1

TABL

E 4. Continued

Cytokin

eSpeciesRegionDetected byC/IRef. IFN yM-CSF M-CS F CSF-

1TGF/32

TGF/ 3Rat Mous e Mous e Mous eMouse Ra tFacial nucleus

Granul

e cell s Ce rBBBCx IH C RNas e protectio n

Si-analysi

sNorthern

Norther

nNorthern /I : axotomy facial nerveC Fro m E D 1 3 t o adulthoo d Durin g developmen t Durin g developmen tC/160 16 1 6 2151
15 1162
Hy , Hypothalamus ; Hip , hippocampus ; Cer , cerebellum ; Cx

, cortex; FCx, frontal cortex; CSF, cerebrospinal fluid; OVLT, organum vasculosumlamina terminalis; BS, brain stem; PVN, paraventricular nucleus; Str, striatum; Thl, thalamus; B, brain (region not specified); ISH, in situhybridization; HC, histochemistry; IHC, immunohistochemistry; IAR, immunoautoradiography; Northern, Northern blot analysis; Western,Western blot analysis; IRMA, immunoradiometric assay; EIMA, enzyme amplified immunometric assay; \ , increased; ED, embryonic day; C/,constitutive expression; C( - ), not found constitutively; I, expression induced by; icv, intracerebroventricular.

1. Endocrine effects on the immune system. Investigations into

th e participatio n o f hormone s i n th e immun e respons e hav e generall y involve d eithe r th e parentera l administratio n o f hormones , antagonists , an d blockers , o r th e ablatio n o f en - docrin e glands . Numerou s report s agre e tha t hormon e ad - ministratio n ca n lea d t o depresse d o r stimulate d immun e responses , dependin g o n th e kin d an d dos e o f hormone s an d th e timin g o f thei r administration . I n general , glucocorti - coids , androgens, progesterone, and ACTH depress the im- mun e respons e in vivo, wherea s GH , PRL , T 4 , an d insuli n increas e th e respons e (168-179) . Gende r difference s i n th e immun e respons e ar e wel l documented . Female s develo p stronge r immun e responses , hav e highe r immunoglobuli n concentrations , an d ar e mor e resistan t t o th e inductio n o f immunologica l toleranc e tha n male s (fo r revie w se e Refs. 170 an d 180)
. Furthermore, the incidence of certain autoimmune disease s i s highe r i n female s (181) . Opioi d peptides , partic - ularl y j3-endorphi n an d Met-enkephalin , hav e als o bee n im - plicate d a s immunomodulator s sinc e the y ca n affec t severa l immun e mechanisms . However , i t i s difficul t t o conclud e whether , a s a whole , thes e peptide s ar e immunosuppressiv e o r immunostimulan t sinc e th e effect s reporte d diffe r de - pendin g o n th e typ e o f immun e proces s studied , o n th e cel l sourc e an d type , o n th e species , o n th e concentratio n o f th e opioi d peptid e used , an d o n experimenta l conditions , i.e. in vivo or in vitro. An analytic discussion of this subject is be- yon d th e scop e o f thi s articl e (fo r revie w se e Refs . 18 0 an d 182)
.

Hypophysectom

y suppresse s hematopoiesi s an d immun e cel l proliferation and causes atrophy of lymphoid organs and a progressiv e deterioratio n o f al l immun e function s (fo r re - vie w se e Ref . 183)
. Immunodeficienc y i n hypophysecto - mize d animal s ca n b e reverse d b y PRL , GH , an d placenta l lactogens , bu t no t b y othe r pituitar y hormone s (176 , 183)
.

Administratio

n o f bromocriptine , whic h specificall y block s PR L release , cause s immunodeficiency . PR L administratio n ha s bee n show n t o revers e thi s effect . Thi s hormon e ha s als o bee n show n t o stimulat e immun e parameter s i n norma l an - imal s (184) . I t ha s bee n show n tha t PR L mRN A i s expresse d i n mito - gen-stimulate d lymphocyte s (74) , and that addition of a spe- cifi c antibod y t o PR L t o th e cultur e mediu m result s i n inhi - bitio n o f lymphocyt e proliferatio n (185) . However , th e inhibitor y effec t o f hypophysectom y o n immun e function s in vivo canno t b e counteracte d b y th e lymphoi d cell-derive d PRL . Th e othe r pituitar y immunostimulator y hormon e i s GH , whic h ha s bee n show n no t onl y t o enhanc e immun eresponses but also to delay aging of the immune system (186) . ACTH has been reported to inhibit different immune function s independentl y fro m it s capacit y t o stimulat e glu - cocorticoi d outpu t (174 , 187)
. Th e inhibitor y effec t o f adrenocorticoi d hormone s i n a variet y o f immun e an d inflammator y mechanism s ha s re - sulte d i n thei r widesprea d therapeuti c application . However, mos t o f th e evidenc e derive s fro m pharmacologica l studies , an d les s i s know n abou t th e effec t o n immun e function s o f fluctuation s o f endogenou s level s o f glucocorticoids . Fo r ex - ample , i n animal s kep t unde r conventiona l condition s bu t withou t furthe r antigeni c stimulation , w e studie d th e rela - tionshi p betwee n endogenou s glucocorticoi d bloo d level s an d th e numbe r o f spleni c B lymphocytes secreting immu- noglobulin s a t a given time (188). A clear inverse relationship betwee n th e value s o f corticosteron e i n bloo d o f adrenalec - tomized , sham-operated , an d stresse d mic e an d th e numbe r o f antibody-secretin g cell s i n th e splee n i s observed . A n approximatel y 10 - t o 15-fol d variatio n i n glucocorticoi d bloo d level s wa s parallele d b y oscillation s o f th e sam e mag - nitud e i n th e numbe r o f antibody-secretin g cell s (10-fold) . Thes e dat a sho w tha t endogenou s level s o f glucocorticoid s contribut e t o the control of B cell activity. Since most immune response s involv e th e cooperatio n betwee n T an d B lym - phocytes , w e ca n conclud e tha t th e pituitary-adrena l axi s affect s th e overal l activit y o f th e immun e system .

2. Neural effects on the immune system. Data on the effects of

autonomi c nervou s syste m mediator s o n th e immun e syste m ar e contradictory , bu t i n th e mai n the y indicat e tha t neuro - transmitter s ca n influenc e th e immun e response , both in vitro an d in vivo (11,16,189-194). We (195) and others (196) have observe d tha t neonata l sympathectom y wit h 6-hydroxy-do - pamin e enhance s th e immun e respons e t o severa l antigens . A simila r effec t wa s als o observe d i n adul t rat s afte r surgica l denervatio n o f th e spleen . However , adul t chemica l sympa - thectom y ha d th e opposit e effec t (197-199) . W e recentl y foun d tha t chemica l denervatio n a t birt h result s i n increase d number s o f immunoglobulin-secretin g cell s i n th e splee n o f adul t mic e tha t wer e kep t unde r conventiona l condition s bu t di d no t receiv e furthe r antigeni c stimulatio n (200) . Becaus e neonata l administratio n o f 6-hydroxydopamin e result s i n a permanen t destructio n o f sympatheti c nerv e endings , th e result s strongl y sugges t tha t ther e i s a permanen t increas e i n th e activit y o f spleni c B lymphocyte s i n mic e deprive d o f sympatheti c innervation . Furthermore , thes e result s agre e wit h th e reporte d enhancin g effect s o f sympathectom y o nDownloaded from https://academic.oup.com/edrv/article/17/1/64/2548532 by guest on 16 August 2023 February, 1996IMMUNE-NEURO-ENDOCRINE INTERACTIONS73 antibody-formin g cell s i n immunize d animals . Sinc e 6

-hydroxy-dopamine administered at birth not only interfereswith the sympathetic innervation of peripheral organs butalso with central noradrenergic neurons, our studies do notallow definitive conclusions about which of these structuresaffects the function of

B cells. However, these studies revealthe relevance of central and autonomic mechanisms in im-munoregulation under basal and activated conditions.

Parasympatheti

c agent s hav e als o bee n reporte d t o affec tantibody formation and cytotoxicity (194, 201
, 202).

Severa

l neuropeptide s ca n affec t immun e cel l activity . Fo rexample, SP enhances B cell production of immunoglobulinM (IgM) and immunoglobulin A (IgA), but not of IgG (203). SO

M and VIP have opposite effects on B cells and also inhibitT cell proliferation (204). SP, SOM, and VIP stimulate mastcells to release mediators of hypersensitivity such as hista-mine and platelet-activating factor (PAF) (205). SP also hasa stimulatory effect on specific immune responses (206-208).The overall picture indicates that, in general, SP exerts stim-ulatory effects while VIP, SOM, and neuropeptide

Y inhibitimmune functions (204, 209-211). Ther e i s als o abundan t evidenc e showin g tha t direc t ma -nipulation of the brain, e.g. electrolytic lesions or stimulationof different parts of th

e brain, can affect the immune response(212-216). The effects on the immune response caused bystress (217-221) and circadian rhythms (222), and the com-plex phenomena of conditioning of the immune response(223-227), also show that processes integrated at the level ofthe CNS can affect immune functions.

3. Immune mechanisms that can be affected by neuro-endocrine

agents. The evidence discussed above shows that hormones, neurotransmitters , an d neuropeptide s ca n affec t th e activit y o f th e immun e system . Mos t o f thes e studie s evaluate d th e influenc e o f neuro-endocrin e signal s o n th e immun e syste m wit h respec t t o eithe r th e proliferatio n o f immun e cell s o r th e fina l effecto r mechanism , suc h a s th e productio n o f antibod - ie s o r th e activit y o f cytotoxi c cells . The generation of specific effecto r cell s an d molecule s o f th e immun e syste m ca n b e influence d a t severa l levels . Thes e level s rang e fro m ver y genera l processes , suc h a s th e intermediat e metabolis m o f immun e cells , t o mor e specialize d mechanisms , suc h a s th e selectio n o f cell s tha t ca n recogniz e a hug e repertoir e o f antigens , an d th e productio n o f th e cytokine s tha t suppor t lymphoi d cel l growt h an d differentiation . Furthermore , th e efficienc y o f a n immun e respons e depend s als o o n th e con - tro l o f processe s suc h a s th e proliferatio n o f cell s wit h lo w affinit y fo r th e antigen , th e interactio n betwee n immun e cell s an d thei r targets , an d th e mobility , migration , an d homin g o f thes e cells . Th e followin g i s a discussio n o n th e effect s o f hormones , neurotransmitters , an d neuropeptide s o n som e o f thes e processes . a. Intermediate metabolism and intracellular signal transduc- tion in immune cells. The control of the metabolism of immune cell s an d th e concentratio n o f secon d messenger s use d fo r intracellula r signa l transduction , e.g. cAMP, can be affected b y neuro-endocrin e signals . Thes e mechanism s ar e speciall y sensitiv e t o neuro-endocrin e signal s du e t o som e peculiari - tie s o f immun e processes . Immun e cell s ar e highl y dependen t o n nutrient s an

dgrowth factors. For example, during an immune response,accessory cells must process the antigen to present it appro-

priatel y t o lymphocytes , whic h transfor m int o blast s an d underg o clona l expansio n afte r receivin g thi s information . Thes e an d othe r immun e processes , suc h a s phagocytosis , cel l migration , an d homing , ar e mechanism s involvin g hig h metaboli c demands . Since lymphocytes are the only cells that nee d t o proliferat e t o reac h th e mas s necessar y t o fulfil l thei r specifi c functions , the y ar e particularl y influence d b y neuro - endocrin e signal s tha t contro l intermediat e metabolis m (228) . Tw o mai n pathways , on e involvin g cAM P an d th e othe r inosito l 1,4,5-triphosphat e (IP 3 ) an d diacylglycero l (DAG ) a s secon d messengers , ar e use d b y hormones , neurotransmit - ters , and neuropeptides for intracellular signal transduction. Ther e i s evidenc e tha t thes e pathway s ar e als o use d b y cer - tai n cytokines , antigens , o r mitogen s whe n the y bin d t o thei r respectiv e receptor s i n immun e cells . Fo r example , bindin g o f a n antige n t o it s specifi c T cel l recepto r (229 ) o r additio n o f IL- 2 t o cel l line s tha t depen d o n IL- 2 fo r growin g (230 ) result s i n activatio n o f phospolipas e C , yielding IP 3 an d DA G a s intracellula r secon d messengers . I t i s als o clea r tha t th e T cel l antige n recepto r an d interleuki n receptor s utiliz e G pro- tein s a s a n initia l transduce r t o amplifie r system s (230) .

Whethe

r thes e G protein s ar e uniqu e o r ar e als o use d b y hormon e receptor s i s no t known . I t i s beyon d th e scop e o f thi s articl e t o revie w thi s matte r i n detai l (fo r revie w se e Refs .

229-232)

. However , i t seem s likel y tha t neuro-endocrin e an d immune-mediate d stimul i shar e mechanism s fo r intracellu - la r signa l transduction . Th e evidenc e i n suppor t o f thi s pos - sibilit y i s still very fragmentary, and much more work is still neede d i n thi s particula r area . Nevertheless , w e wis h t o em - phasiz e thi s aspec t her e sinc e immun e cell s ar e probably , excep t fo r neurons , th e cell s tha t ar e expose d t o th e mos t diversifie d arra y o f signal s fro m insid e an d outsid e th e or - ganism . Furthermore , sinc e immun e cell s ar e mobile , the y ar e als o expose d t o locall y generate d mediator s i n th e dif - feren t microenvironement s wher e the y circulat e o r ar e lo - cated . Th e commo n us e o f intracellula r transductio n signal s b y hormones , neurotransmitters , neuropeptides , an d im - mun e ligand s woul d provid e a molecula r basi s fo r syner - gisti c an d antagonis t effect s o f neuro-endocrin e an d immun e agent s o n th e immun e response . In addition, the convergence o f differen t type s o f stimul i tha t d o no t shar e th e sam e in - tracellula r signalin g pathwa y ma y contribut e t o interaction s betwee n immun e an d neuro-endocrin e agents . Fo r example , stimulatio n o f th e T cel l recepto r result s i n activatio n o f th e phosphoinositid e pathwa y withou t affectin g th e level s o f cAMP . However, the increase in intracellular levels of cAMP induce d b y stimulatio n o f /3-adrenergi c receptor s i n lym - phocyte s i s furthe r enhance d i f th e T cel l recepto r i s als o stimulate d (229) . Sinc e a n increas e i n intracellula r cAM P level s inhibit s proliferation , thi s ma y explai n th e fac t tha t stimulatio n o f /3-adrenergi c receptor s a t th e tim e o f lympho - cyt e activatio n ultimatel y result s i n a decrease d proliferativ e response . I n summary , th e outcom e o f th e biochemica l event s ini - tiate d i n a lymphocyt e afte r recognitio n o f a n antige n o r induce d b y a cytokin e would , i n fact , depen d o n othe r in - tracellula r signal s resultin g fro m th e simultaneou s bindin gDownloaded from https://academic.oup.com/edrv/article/17/1/64/2548532 by guest on 16 August 2023

74BESEDOVSKY AND DEL REYVol. 17, No. 1

o f neuro-endocrin e ligand s tha t occu r unde r physiologica l o r pathologica l conditions . b. Negative and positive selecti