ommunication between theneuroendocrine and im-mune systems is commonlyassociated with release of

humoral factors such as cortisol and epinephrine from the hypothalamic–pituitary–adrenal (HPA) axis1,2 (Fig. 1).However, it was anticipated that a neuronalcontrol system also plays an important rolein communication2,3. It has been known forover a century that transcutaneous electricalstimulation of the enlarged spleen in pa-tients with leukaemia leads to a reduction oforgan size and an increase in blood leuko-cyte counts4. These experiments suggested afunctional innervation of the spleen, and inthe 80s, immunohistochemical studies demonstrated the close asso-ciation of autonomic nerve terminals with macrophages and lym-phocytes (reviewed in Ref. 3). The morphology of these contacts is indicative of a chemically mediated transmission between nervesand immune cells (Fig. 1).

In this article, we examine whether the criteria for chemicallymediated transmission between nerve terminals and immune cellsin lymphoid organs are met (see Box 1). The local regulation of thenerve–immune cell dialogue will be outlined taking splenic inter-leukin 6 (IL-6) production as an example. Finally, the significance of the dialogue for the development of immune responses is discussed.

The association between nerve terminals and immune cells in the spleenNeurotransmitter synthesis, storage and releaseIn the splenic nerve, for example, norepinephrine (NE) is synthe-sized and stored in the nerve terminal6 (Fig. 2). Neuropeptides, suchas neuropeptide Y (NPY) (Ref. 7), are synthesized in the soma ofsplenic nerves, transported via the axon, and are also stored in thenerve terminal. NE, NPY and opioids are produced in the samenerve and are colocalized in the nerve terminal8. Furthermore, inimmunohistochemical studies acetylcholine (not in the spleen), calcitonin gene-related peptide (CGRP), somatostatin, substance Pand vasoactive intestinal peptide (VIP) were detected in lymphoidorgans2,12.

In vivo microdialysis studies have demonstrated significant NErelease from the spleen13. In situ perfusion studies of the porcine

spleen with electrical stimulation of thepostganglionic splenic nerves led to the ef-flux of NE and NPY (Ref. 7). In addition, invitro superfusion experiments using spleenslices demonstrated neural release of NE(Refs 9–11) and endogenous opioid pep-tides11. All these techniques demonstratedinducible NE release in a similar way, whichindicates that slice superfusion is as valid asin vivo or in situ methods. Although trans-mitters other than NE, NPY or opioids werenot analyzed in these experiments, it is verylikely that other neuropeptides such asCGRP, somatostatin, substance P and VIP inthe nerve fibres of lymphoid organs are alsoreleased. In less than 1% of cases (E. Weihe,

pers. commun.), nerve endings terminate at immune cells forming asmall cleft of less than 10 nm (Ref. 3). Upon release, the transmittersdiffuse to target immune cells in the local microenvironment andbind to specific surface receptors, thus leading to chemically medi-ated transmission.

Neurotransmitters are bound and recognized by receptors on immune cells and have functional significanceIt is well established that immune cells can bind different neurotransmitters and neuropeptides1,2,12,14. For example, receptorsfor adrenergic agents, adenosine, acetylcholine, endorphins, en-kephalins, substance P, somatostatin and VIP have been demon-strated on immune cells (reviewed in Refs 1, 2, 12, 14). Adrenergicand opioidergic receptors have been found on lymphocytes, granu-locytes, monocytes, macrophages and natural killer cells1,2,12,14,15

(Fig. 2). For example, ligation of b-adrenoceptors on lymphocytesleads to an increase in intracellular cyclic AMP (cAMP) concen-tration16 and, since the first studies in the 70s, it has been demon-strated that this can alter immune functions such as mitogen-induced proliferation and antibody production17. Furthermore, ac-cumulation of cAMP reduces synthesis of tumour necrosis factor a(TNF-a) (Refs 18, 19), IL-2 (Ref. 20), interferon g (Refs 21, 22) andIL-12 (Refs 23, 24), but cAMP accumulation stimulates IL-4 (Ref. 25),IL-5 (Refs 25–27), IL-6 (Ref. 28) and IL-10 (Refs 29, 30). Thus, li-gation of neurotransmitter receptors that stimulate the adenylatecyclase leads to a shift towards T helper 2 (Th2)-type responses,whereas downregulation of intracellular cAMP stimulates a Th1-type response31.

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V o l . 1 9 N o . 9 4 0 9

Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0167-5699/98/$19.00

S E P T E M B E R 1 9 9 8

Dialogue between the CNS and theimmune system in lymphoid organs

Rainer H. Straub, Jürgen Westermann, Jürgen Schölmerich and Werner Falk

It is well known that the CNS

influences the responses of the

immune system via humoral

substances such as cortisol. Here,

Rainer Straub and colleagues

discuss aspects of the local

interaction between nerves and

immune cells in lymphoid organs.

They provide evidence for

chemically mediated transmission

between nerves and immune cells

in the spleen which is modified by

the microenvironment.

PII: S0167-5699(98)01297-3

C

The chemically mediated signal transmission can be blocked bycompetitive antagonistsIt can be shown that macrophages in murine spleen slices sponta-neously secrete IL-6 (Refs 9–11, 32) and this can be inhibited follow-ing electrically induced release of NE and opioids. The level of IL-6secretion following electrical stimulation can be partly restored byspecific competitive antagonists of adrenergic and opioidergic re-ceptors9–11, confirming the role of these molecules in the IL-6 response. Administration of a combination of a-adrenergic and m-opioidergic receptor antagonists nearly completely restored the

electrically induced inhibition of IL-6 secre-tion11. Thus, both endogenous norepineph-rine and endogenous opioids (most likely b-endorphin) can inhibit macrophage IL-6secretion under specific conditions11. Elec-trical field stimulation used in these ex-periments is not restricted to neurotransmit-ter release. However, relatively roundparticles such as macrophages, lympho-cytes and synaptosomes, compared withnerve fibres, form a Faraday cage with anegative charge at the surface which mainlyexcludes a direct effect of the electrical cur-rent on immune cells (E.A. Singer, pers.commun.).MThus, the criteria usually applied to de-fine chemically mediated transmission (Box1) are met for the nerve–immune cell inter-action in lymphoid organs. Furthermore,the experimental data indicate that this in-teraction is not only directed from nerves toimmune cells, but also allows bidirectionaltraffic33.

The function of nerve terminalscan be modulated by targetimmune cellsThe function of the nerve terminals is con-trolled by autoreceptors, a mechanism bywhich the released transmitter modulatesits own release (Fig. 2). In addition, trans-mitter release can be modulated by othersubstances via heteroreceptors (Fig. 2, re-viewed in Ref. 34). It has been shown thatcytokines produced by macrophages andlymphocytes, such as IL-1, IL-2, IL-6 andTNF-a, can inhibit NE release from pre-synaptic varicosities35–37 (Table 1). Further-more, these cells can also produce adreno-corticotropic hormone38, opioids38 andacetylcholine40, which can alter neural NErelease39,41,42 (Table 1).MIn addition to efferent nerve terminals,

lymphoid organs contain afferent nerve fibres43, which have recep-tors for cytokines or other molecules produced by immune cells44,45.By binding to such receptors, locally produced IL-1b bypasses theblood brain barrier46, and causes the CNS to elevate the systemiccortisol levels (via the HPA axis47) and to increase the efferent activ-ity of the sympathetic splenic nerves (via the hypothalamus–auto-nomic nervous system axis48). This activation is blocked when theafferent fibres of the vagal nerve are disrupted47,48. Moreover, it wasshown that immune cells in inflamed hind paws of rats secrete b-endorphin which binds to nerve terminals of sensory neurons leading

V I E W P O I N TI M M U N O L O G Y TO D AY

4 1 0 V o l . 1 9 N o . 9S E P T E M B E R 1 9 9 8

Fig. 1. Communication pathways between the nervous and immune systems. The left panel repre-sents the humoral HPA axis regulating the systemic concentration of cortisol and epinephrine (redlines). The right panel demonstrates the efferent neuronal hypothalamus–autonomic nervous sys-tem axis locally influencing immune function via neurotransmitters in lymphoid organs and in-flamed tissue (blue lines). In addition, the cytokines IL-1, IL-6 and TNF-a modulate the CNS eitherdirectly or via receptors on sensory afferents such as the vagal nerve (feedback mechanisms, for ex-ample in inflamed tissue: green lines). These afferent sensory nerves are also present in lymphoidorgans (not shown). Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; HPA, hypothalamus–pituitary–adrenal axis; IL-1, interleukin 1; TNF-a, tumournecrosis factor a.

Humoral

CRH

ACTH

Cortisol, epinephrine

Hypothalamus

Spleen

IL-1 IL-6TNF-α

Lymphnode

Inflamedtissue

Pituitary

Adrenal gland

Via

the

bloo

d st

ream

Via

sen

sory

affe

rent

s

Neuronal

to a local analgesic response44,45. Thus, besides the local modulationof immune cell function by nerve terminals, there is clear evidencethat local products of immune cells influence the function of thenerve terminal either directly through presynaptic receptors or cen-trally via the CNS by binding to receptors expressed on afferentnerve fibres46,47,49.

Splenic IL-6 production: local neuronal control andfine tuning by the microenvironmentIL-6 is a pleiotropic cytokine with multiple immunomodulatory ef-fects (reviewed in Ref. 50). Among its targets are B cells, T cells andhaematopoietic stem cells50. IL-6 has an important role in the acutephase response51 and it is a mediator of glucocorticoid productionvia the HPA axis50. Using a microchamber superfusion technique, it can be shown that IL-6 secreted by murine splenic macrophagesis a reliable parameter of local nerve–immune cell communi-cation9–11,32. Electrical field stimulation elicited large amounts of neurally located NE (Ref. 9) and b-endorphin (R.H. Straub, un-published) and was accompanied by inhibition of spontaneoussplenic IL-6 secretion9–11,32. This inhibition was abrogated by com-petitive antagonists of adrenergic and opioidergic receptors9–11, thuscorroborating that spontaneous splenic IL-6 production is underadrenergic and opioidergic neural control9–11 (Table 2).

The situation becomes even more complex because the effect ofneurally released neurotransmitters depends on the microenviron-ment of the nerve–immune cell contact region. In a bacteria-free en-vironment, cortisol in the superfusion medium increased IL-6 secre-tion through b-adrenergic-dependent mechanisms and led to aninhibition of IL-6 secretion by opioidergic mechanisms32 (Table 2). Inthe presence of bacteria in the spleen slice, NE inhibited IL-6 secretionthrough b-adrenergic receptors, whereas in the absence of bacteriathis was not the case10 (Table 2). In all cases, IL-6 secretion is inhibitedby electrical field stimulation, which indicates the general inhibitoryaction of the sympathetic nervous system in the spleen (Table 2).

There are further complexities of this local fine tuning: receptorsare up- and downregulated depending on the nerve firing ratewhich controls the local concentration of endogenous agonists (de-sensitization)52. In addition, receptor density and receptor subtypescan be regulated by other substances, for example cortisol34, which increases b-adrenergic receptor density. Owing to the differ-ent expression of the receptors on the various immune cells, these

V I E W P O I N TI M M U N O L O G Y TO D AY

V o l . 1 9 N o . 9 4 1 1S E P T E M B E R 1 9 9 8

Box 1. The nerve–immune cell interaction meets the criteria for chemically mediated

transmissiona

• Synthesis of the neurotransmitter in the postganglionicnerve6 and storage in the nerve terminal2,7,8

• Release of the neurotransmitter into the vicinity of the nerveterminal7–11

• Binding and recognition of the neurotransmitter by targetcell receptors2,12

• Blocking of the action of the endogenous neurotransmitterby competitive antagonists9–11

aRef. 5.

Fig. 2. Local dialogue between a nerve terminal and a macrophage in thespleen. Upon an action potential (step 1), NE is released from nerve termi-nals into the surrounding area (step 2). Neural NE binds to adrenergic receptors at the macrophage membrane (step 3). The binding of NE toadrenergic receptors decreases IL-6 secretion from macrophages (step 4).Released NE can negatively regulate its own release via autoreceptors onthe nerve terminal (step 5). NE release is also regulated, for example, byTNF-a via heteroreceptors (step 6). Arrows demonstrate a positive influ-ence and bars a negative influence (only adrenergic mechanisms delin-eated). Abbreviations: IL-6, interleukin 6; NE, norepinephrine; TNF-a,tumour necrosis factor a.

IL-6

Macrophage

α1 α2

α2

TNF-α

β1

NE

β2

1

23

6

4

5

Table 1. Norepinephrine release by nerveterminals is influenced by substances produced bytarget immune cells

Substancesa Effect on NE release Refs

IL-1b (Macrophage) ↓ 35, 36IL-2 (T cell) ↓ 36IL-6 (Macrophage) ↓ 35TNF-a (Macrophage) ↓ 37ACTH

(Blood leukocytes) ↑ 38, 39Acetylcholine

(Blood leukocytes) ↓ (M2 muscarinicb) 40, 41↑ (M1 muscarinicb)

Opioids ↓ (d-opiodergicb) 38, 42(Blood leukocytes) ↓ (k-opiodergicb)

Abbreviations: ACTH, adrenocorticotropic hormone; IL-1b, interleukin1b; NE, norepinephrine; TNF-a, tumour necrosis factor a.aThe main producers of substances are given in parentheses.bSubtypes of cholinergic and opioidergic receptors.

respond individually and differentially to nerve actions so that different types of immune reactions can emerge2,53.

ConclusionsThe CNS influences the immune system in a more general fashionby regulating the systemic concentration of humoral substancessuch as cortisol and epinephrine, whereas the autonomic nervoussystem communicates specifically with the immune system accord-ing to local conditions. It seems very likely that more examples ofsuch specific local interaction between the autonomic nervous sys-tem and the immune system will become obvious in the future.Since macrophage-derived IL-6 polarizes naive T cells to become ef-fector Th2 cells54, the neuroendocrine regulation of IL-6 productionby antigen-presenting macrophages would be a key factor in deter-mining the type of immune response54,55. Modulating the nervoussystem, either centrally by psychopharmacological drugs or locally,at the synaptic level, by transmitter antagonists, agonists and uptake-blockers, might be a promising approach for immune ther-apy. Thus, the local interaction of the autonomic nervous systemand the immune system in lymphoid organs and nonlymphoid tissues represents the rationale for treating selected inflammatory diseases by neuropharmacological or psychological intervention.

We thank all of our colleagues in the Dept of Internal Medicine I for

their continuous support. We gratefully acknowledge T.J. Feuerstein and

H.H. Peter, Freiburg; and R. Pabst and M. Schedlowski, Hannover, for their

critical comments.

Rainer Straub (Rainer.Straub@klinik.uni-regensburg.de), JürgenSchölmerich and Werner Falk are at the Laboratory of Experimental

Neuroendocrinoimmunology, Dept of Internal Medicine I, University ofRegensburg, D-93042 Regensburg; Jürgen Westermann is at the Centreof Anatomy, Medical School of Hannover, D-30623 Hannover, Germany.

References1 Blalock, J.E. (1994) Immunol. Today 15, 504–511

2 Besedovsky, H.O. and Del Rey, A. (1996) Endocr. Rev. 17, 64–102

3 Felten, D.L., Felten, S.Y., Bellinger, D.L. et al. (1987) Immunol. Rev. 100,

225–260

4 Botkin, S. (1874) Die Contractilität der Milz und die Beziehung der

Infectionsprocesse zur Milz, Leber, den Nieren und dem Herzen, August

Hirschwald Verlag

5 Eruklar, S.D. (1994) in Basic Neurochemistry: Molecular, Cellular and

Medical Aspects (Siegel, G.J., Agranoff, B.W., Albers, R. and Molinoff, P.B.,

eds), pp. 181–208, Raven Press

6 Euler, U.S. and Hilarp, N.A. (1956) Nature 177, 44–45

7 Lundberg, J.M., Rudehill, A., Sollevi, A., Fried, G. and Wallin, G. (1989)

Neuroscience 28, 475–486

8 Fried, G., Terenius, L., Brodin, E. et al. (1986) Cell Tissue Res. 243, 495–508

9 Straub, R.H., Lang, B., Falk, W., Schölmerich, J. and Singer, E.A. (1995)

J. Neuroimmunol. 61, 53–60

10 Straub, R.H., Herrmann, M., Frauenholz, T. et al. (1996)

J. Neuroimmunol. 71, 37–43

11 Straub, R.H., Herrmann, M., Berkmiller, G. et al. (1997) J. Neurochem. 68,

1633–1639

12 Madden, K.S. and Felten, D.L. (1995) Physiol. Rev. 75, 77–106

13 Shimizu, N., Hori, T. and Nakane, H. (1994) Brain Behav. Immun. 8,

14–23

14 Carr, D.J.J. (1992) Chem. Immunol. 52, 84–105

15 Jetschmann, J.U., Benschop, R.J., Jacobs, R. et al. (1997) J. Neuroimmunol.

74, 159–164

16 Bourne, H.R., Lichtenstein, L.M., Melmon, K.L., Henney, C.S.,

Weinstein, Y. and Shearer, G.M. (1974) Science 184, 19–28

17 Watson, J. (1975) J. Exp. Med. 141, 97–111

18 Katakami, Y., Nakao, Y., Koizumi, T., Katakami, N., Ogawa, R. and

Fujita, T. (1988) Immunology 64, 719–724

19 Renz, H., Gong, J.H., Schmidt, A., Nain, M. and Gemsa, D. (1988)

J. Immunol. 141, 2388–2393

20 Novogrodsky, A., Patya, M., Rubin, A.L. and Stenzel, K.H. (1983)

Biochem. Biophys. Res. Commun. 114, 93–98

21 Reizin, F.N., Roikhel, V.M. and Chumakov, M.P. (1975) Arch. Virol. 49,

307–315

22 Ivashkiv, L.B., Ayres, A. and Glimcher, L.H. (1994) Immunopharmacology

27, 67–77

23 van der Pouw Kraan, T.C., Boeije, L.C., Smeenk, R.J., Wijdenes, J. and

Aarden, L.A. (1995) J. Exp. Med. 181, 775–779

24 Aloisi, F., Penna, G., Cerase, J., Menendez, I.B. and Adorini, L. (1997)

J. Immunol. 159, 1604–1612

25 Lacour, M., Arrighi, J.F., Muller, K.M., Carlberg, C., Saurat, J.H. and

Hauser, C. (1994) Int. Immunol. 6, 1333–1343

26 Lee, H.J., Koyano-Nakagawa, N., Naito, Y. et al. (1993) J. Immunol. 151,

6135–6142

27 Siegel, M.D., Zhang, D.H., Ray, P. and Ray, A. (1995) J. Biol. Chem. 270,

24548–24555

28 Zhang, Y., Lin, J-X. and Vilcek, J. (1988) J. Biol. Chem. 263,

6177–6182

29 Platzer, C., Meisel, C., Vogt, K., Platzer, M. and Volk, H.D. (1995)

Int. Immunol. 7, 517–523

V I E W P O I N TI M M U N O L O G Y TO D AY

4 1 2 V o l . 1 9 N o . 9S E P T E M B E R 1 9 9 8

Table 2. The microenvironment modulates theregulation of splenic IL-6 production at the nerveterminal–macrophage contact sitea

Condition in the Receptors involved and effect microenvironment on splenic IL-6 secretion

Cortisol Bacteria Receptor Effectb

None None b-adrenergic 5a2-adrenergic ↓m-opioidergic ↓

Present None b-adrenergic ↑a2-adrenergic ↑m-opioidergic ↓

None Present b-adrenergic ↓a2-adrenergic ↓m-opioidergic ND

Present Present b-adrenergic ↓↓a2-adrenergic NDm-opioidergic ND

aRefs 9–11, 32.b5, no effect; ↑ , stimulating effect; ↓ , inhibiting effect; ↓↓ , strongly inhibitingeffect; ND, not determined.

V I E W P O I N TI M M U N O L O G Y TO D AY

V o l . 1 9 N o . 9 4 1 3S E P T E M B E R 1 9 9 8

30 Eigler, A., Siegmund, B., Emmerich, U., Baumann, K.H., Hartmann, G.

and Endres, S. (1998) J. Leukocyte Biol. 63, 101–107

31 Munoz, E., Zubiaga, A.M., Merrow, M., Sauter, N.P. and Huber, B.T.

(1990) J. Exp. Med. 172, 95–103

32 Straub, R.H., Dorner, M., Riedel, J. et al. (1998) Am. J. Physiol. 274,

R997–R1003

33 Blalock, J.E. (1984) J. Immunol. 132, 1067–1070

34 Powis, D.A. and Bunn, S.J., eds (1995) Neurotransmitter Release and its

Modulation, Cambridge University Press

35 Ruhl, A., Hurst, S. and Collins, S.M. (1994) Gastroenterology 1077,

993–1001

36 Bognar, I.T., Albrecht, S.A., Farasaty, M., Schmitt, E., Seidel, G. and

Fuder, H. (1994) Naunyn Schmiedeberg’s Arch. Pharmacol. 349, 497–502

37 Soliven, B. and Albert, J. (1992) J. Neurochem. 58, 1073–1078

38 Blalock, J.E. and Smith, E.M. (1980) Proc. Natl. Acad. Sci. U. S. A. 77,

5972–5974

39 Gothert, M. and Hentrich, F. (1984) Naunyn Schmiedeberg’s Arch.

Pharmacol. 328, 127–134

40 Rinner, I. and Schauenstein, K. (1993) J. Neurosci. Res. 35, 188–191

41 Starke, K., Gothert, M. and Kilbinger, H. (1989) Physiol. Rev. 69, 864–989

42 Fredholm, B.B. (1995) in Neurotransmitter Release and its Modulation

(Powis, D.A. and Bunn, S.J., eds), pp. 104–121, Cambridge University Press

43 Elfvin, L.G., Aldskogius, H. and Johansson, J. (1992) Cell Tissue Res. 269,

229–234

44 Stein, C., Hassan, A.H., Przewlocki, R., Gramsch, C., Peter, K. and

Herz, A. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 5935–5939

45 Cabot, P.J., Carter, L., Gaiddon, C. et al. (1997) J. Clin. Invest. 100,

142–148

46 Niijima, A. (1996) J. Auton. Nerv. Syst. 61, 287–291

47 Fleshner, M., Goehler, L.E., Hermann, J., Relton, J.K., Maier, S.F. and

Watkins, L.R. (1995) Brain Res. Bull. 37, 605–610

48 Niijima, A., Hori, T., Aou, S. and Oomura, Y. (1991) J. Auton. Nerv. Syst.

36, 183–192

49 Watkins, L.R., Goehler, L.E., Relton, J.K. et al. (1995) Neurosci. Lett. 183,

27–31

50 Kishimoto, T. (1989) Blood 74, 1–10

51 Tilg, H., Dinarello, C.A. and Mier, J.W. (1997) Immunol. Today 18,

428–432

52 Sibley, D.R. and Lefkowitz, R.J. (1985) Nature 317, 124–129

53 Sanders, V.M., Baker, R.A., Ramer-Quinn, D.S., Kasprowicz, D.J.,

Fuchs, B.A. and Street, N.E. (1997) J. Immunol. 158, 4200–4210

54 Rincon, M., Anguita, J., Nakamura, T., Fikrig, E. and Flavell, R.A. (1997)

J. Exp. Med. 185, 461–469

55 Abbas, A.K., Murphy, K.M. and Sher, A. (1996) Nature 383, 787–793

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