Posttraumatic stress and immune dissonance

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Chinese Journal of Traumatology 2008; 11(4):203-208

Special column of 10th anniversary

Posttraumatic stress and immune dissonance JIANG Jian-xin 蒋建新* Stress or neuroendocrine response usually occurs soon after trauma, which is central to the maintenance of posttraumatic homeostasis. Immune inflammatory response has been recognized to be a key element both in the pathogenesis of post-traumatic complications and in tissue repair. Despite the existence of multiple and intricate interconnected neuroendocrine pathways, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system have been considered to be the most important in trauma. Although the short-term and appropriate activation of these stress responses is vital to the host’s adaptation, prolonged duration and exaggerative magnitude of their activity leads to deleterious effects on immune function in trauma, causing immune dissonance. The overall appropriate and con-

trolled activation and termination of the neuroendocrine responses that mediate the necessary physiological functions involved in maintaining and restoring homeostasis in the event of trauma are of critical importance. This review will describe the effects of some important neuroendocrine responses on immune system. Present evidences indicate that the neuroendocrine and immune systems form a cohesive and integrated early host response to trauma, and identify areas for further research to fully elucidate the regulatory role of neuroencrine system in trauma. Key words: Stress; Neuro secretory systems; Immune system; Wounds and injuries

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thal effects, including development of traumatic complications 1 and delayed wound healing 2.

ost-traumatic stress response, which occurs immediately after trauma, is a complex adaptive phenomenon, involving the synchronized interaction of multiple neuronal and endocrine pathways geared at restoring homeostasis. Immune inflammatory response has been recognized to be a key element both in the pathogenesis of post-traumatic complications and in tissue repair. It has been demonstrated that there is bidirectional network between neuroendocrine and immune systems. Although this interaction constitutes a pivotal feedback loop that optimizes immune inflammatory responses after trauma, prolonged or inappropriate neuroendocrine responses might also predispose the host to excess inflammation or uncontrolled infection, finally leading to pathological and le-

State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital/ Institute of Surgery Research, Third Military Medical University, Chongqing 400042, China (Jiang JX) *Corresponding author: Tel: 86-23-68757401, E-mail: [email protected] This work was supported by the Major State Basic Research Development Program of China (No. 2005CB 522602) and the Key Research Project of the “Eleventh Five-Year Plan” of PLA (No. 06G080)

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Neuroendocrine regulation of immunity occurs through systemic, regional and local routes. 3 The local route, peripheral nervous system, regulates local inflammatory responses through the release of neuropeptides in local injury area. The sympathetic (or adrenergic) nervous system (SNS) and the parasympathetic (or cholinergic) nervous system modulate inflammation through innervation of immune organs at a regional level. Neuroendocrine responses control inflammation at a systemic level by the hypothalamic-pituitary-adrenal (HPA) axis through glucocorticoids released from the adrenal cortex, by the hypothalamic–pituitary–gonadal (HPG) axis through sex hormones released from the ovaries and testes, and by the hypothalamic–pituitary– thyroid hormone axis through thyroid hormones released from the thyroid gland. Despite the multiple and intricate interconnected pathways, the two pathways at the core of the stress system wiring are the HPA axis and the SNS. The core function of the HPA and SNS pathways is central to the host’s adaptation to acute challenges by ensuring energy substrate mobilization, car-

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diovascular and hemodynamic compensation, increasing awareness, and subsequently by contributing to host immune function and tissue repair. Although the shortterm and appropriate activation of these stress responses is vital to the host’s adaptation, prolonged duration and increased magnitude of their activity lead to deleterious effects on immune function in trauma,4 causing immune dissonance. Thus, the overall appropriate and controlled activation and termination of the neuroendocrine responses that mediate the necessary physiological functions involved in maintaining and restoring homeostasis in trauma are of critical importance. This review will describe the effects of some important neuroendocrine responses on immune system. Present evidences indicate that the neuroendocrine and immune systems form a cohesive and integrated early host response to trauma, and identify areas for future research to fully elucidate the regulatory role of neuroendocrine system in trauma. Regulatory role of hypothalamic-pituitary-adrenal (HPA) axis on immune system HPA consists of a set of brain regions (the hypothalamus) and endocrine organs (the pituitary and cortex of the adrenal glands). In response to stress, corticotropin-releasing hormone (CRH) is first secreted from cells of the paraventricular nucleus of the hypothalamus into the hypophyseal blood supply around the pituitary gland. CRH then stimulates the release of adrenocorticotropic hormone from the anterior pituitary into the blood, which in turn stimulates the synthesis and release of endogenous glucocorticoids from the adrenal cortex. The glucocorticoids are the effector hormones for HPA. In addition to their role in maintaining metabolic homeostasis, glucocorticoids are essential for the modulation of immune functions in both acute and chronic stresses.5 In general, glucocorticoids have been considered as an immune suppressor. Fluctuations in the levels of circulating glucocorticoids, such as circadian variations or fluctuations that occur after stress, have been shown to be correlated with decreases in IL-1 β and tumornecrosis factor (TNF) production by leukocytes. 6,7 Furthermore, glucocorticoids have been shown to suppress maturation, differentiation and proliferation of all immune cells, including dendritic cells (DCs) and macrophages. Glucocorticoids inhibit DC differentiation depending on the stage of maturation.8 Glucocorticoids

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also reduce t he capacity of DCs to promote allostimulatory responses and efficient activation of naive T cells in vitro, possibly owing to downregulation of expression of MHC class II and co-stimulatory molecules. 9 In vivo, dexamethasone (a synthetic glucocorticoid) impairs the ability of rat thymic DCs to produce IL-1βand TNF, but not IL-10.10 Dexamethasone also inhibits IL-12p40 production by LPS-stimulated human monocytes by downregulation of activation of JUN N-terminal kinase (JNK), mitogen-activated protein kinase (MAPK), activator protein 1 (AP1) and nuclear factor-κB (NF-κB).11 In addition, glucocorticoids could cause a shift in adaptive immune responses from a T helper 1 (TH1) type to a TH2 type, which is largely through inhibiting the production of the TH1-cellinducing cytokine interleukin-12 (IL-12) by DCs and macrophages. 12 With respect to effects on immunecell trafficking, glucocorticoids have been shown to inhibit the expression of many cell-adhesion molecules involved in cell trafficking, including intracellular adhesion molecule 1 (ICAM1), endothelial-leukocyte adhesion molecule 1 (ELAM1), also known as E-selectin and vascular adhesion molecule 1 (VCAM1). 13,14 Glucocorticoids also inhibit the production and secretion of chemokines, such as CC-chemokine ligand 2 (CCL2, or MCP1) and CXC-chemokine ligand 8 (CXCL8, or IL-8) by eosinophils, as well as chemoattractant IL-5 by mast cells and T cells. 15 In addition, dexamethasone can downregulate T-cell expression of CCL8 (also known as MCP2) and CCL7 (also known as MCP3), which are chemotactic for many cell types including monocytes, DCs, and natural killer cells. 16 In addition to their immunosuppression, glucocorticoids, at some circumstances, have been shown to enhance immune function. Results from our lab recently have indicated that corticosterone in vitro could enhance phagocytosis and chemotaxis of mouse peritoneal macrophages in a lower concentration (≤50 ng/ml) and for short duration of stimulation. At this case, cortisosterone also enhances the capacity of macrophages to produce TNF-α.17 Dhabhar18 further indicated that glucocorticoids could increase delayed-type hypersensitivity in physiological concentrations. Some other reports have indicated that the physiological role of endogenous glucocorticoids might be distinct from the effects of therapeutic concentrations of synthetic cortisol analogues. For example, dexamethasone suppression of IL-6 production has been reported, but the en-

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dogenous glucocorticoid, cortisol, is 25 times less effective than synthetic cortisol analogues in suppressing the cytokine. Suppression of IL-6 by cortisol only occurr at concentrations that are never attained in vivo. 19 Furthermore, inhibition of NF-κB requires high concentrations of dexamethasone (1×10-6–1×10-7 mol/L dexamethasone in vitro or 1 mg/kg in vivo) comparable to those obtained by high-dose daily or pulse glucocorticoid (GC) therapy. In addition, interruptions of the HPA axis, through surgical interventions (adrenalectomy or hypophysectomy) or through pharmacological intervention with glucocorticoid antagonists (such as RU486), renders otherwise relatively inflammation-resistant animals highly susceptible to both endogenous and exogenous bacterial infection.20-22 Conversely, reconstitution of the HPA axis treated with exogenous glucocorticoids or by hypothalamic transplantation reverses this effect and prevents mortality in these animal models. 20-23 The above data indicate that glucocorticoids might have dual effects on immune system, which largely depends upon the magnitude and duration of stress. Regulation of sympathetic nervous system on immune systems The SNS regulates immune system through the innervation of immune organs and the release of noradrenaline at a regional level, and through the release of adrenaline from the medulla of the adrenal glands at a systemic level. In lymphoid tissues, both lymphocytes and macrophages are adjacent to neuronal fibers, exposing them to local release of neuropeptides forming synaptic-like neuroimmune interactions, allowing modulation of localized inflammatory responses through direct neural release and humoral neuroendocrine mediators. The local release of neuroendocrine mediators coupled with specific receptor expression in immune cells establishes a functional neuroimmune connection capable of modulating various immune responses, including cytokine production, neutrophil chemotaxis, phagocytosis, and reactive oxygen species production and release.4 There are more and more evidences indicating that SNS exerts an important modulation on immune system, showing immunosuppressive in most studies. In vitro, noradrenaline mediates its immunosuppressive effects on DCs and monocytes by inhibiting LPS-induced production of TNF, 24 IL-12, 25 and macrophage inhibitory protein 1 α 26 and enhance LPS-stimulated

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release of IL-10. 27 Pharmacological blockade of adrenergic receptors potentiates IL-6 secretion and inhibits IL-10 secretion in vivo. The peritoneal macrophages obtained from sympathectomized mice can increase TNF-αproduction in response to LPS stimulation. Noradrenaline also increases the secretion of the chemotactic chemokine CXCL8 by fibroblasts isolated from patients with rheumatoid arthritis and promotes the migration of NK cells, monocytes and macrophages, but inhibits DC migration in vitro. 28 Noradrenaline inhibits the in vitro DC chemotactic response to the chemokines CCL19 and CCL21 (which are important for DC migration from the site of antigens to regional lymph nodes), through upregulation of anti-inflammatory IL-10 production. In vivo studies have shown that catecholamines affect dendritic cell function, enhancing myelopoiesis and suppressing lymphopoiesis through specific adrenergic receptor mechanisms.29 Results from interruptions of SNS by chemical sympathectomy or by surgically cutting sympathetic nerve innervation of lymphoid organs further demonstrate the role of SNS in regulating immunity at a regional level. The removal of tissue norepinephrine stores could result in an exacerbated rise in lung TNF expression and NF-κB activation after hemorrhagic shock and fluid resuscitation. 30 However, results from our lab recently indicated that short exposure of mouse peritoneal macrophages to lower concentration of noradrenaline or adrenaline could lead to increases in cytokine production, chemotaxis, adhesion and phagocytosis. In addition, such a treatment could also enhance LPS-induced cytokine production. Some other studies also show that catecholamines and SNS activation could increase immune and pro-inflammatory responses at some circumstances. 31,32 These conflictive conclusions have been explained partially by different effects mediated by the specific receptor subtypes. Catecholamines act on their target cells by binding to cell surface adrenergic receptors. Reports indicate that α-and β-adrenergic receptors are expressed in immune cells, withβ-adrenergic receptors having a wider expression in these cells. Catecholamines have been considered to suppress pro-inflammatory cytokine production through β-adrenergic receptors, but enhance pro-inflammatory cytokine production throughα-adrenergic receptors. 33 In addition, regulation of catecholamines on immune cells also depends on the type of cells and the stimulation conditions of the hormones.

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Parasympathetic control of immunity The parasympathetic nervous system modulates immune responses at a regional level through both the efferent and afferent fibres of the vagus nerve. The afferent fibres of the vagus nerve can signal the presence of peripheral inflammation to the brain. It has been demonstrated that pro-inflammatory cytokines, such as IL-1 released by activated innate immune cells in local tissues, bind to cytokine receptors on the surfaces of paraganglia cells, activate afferent fibres of the vagus nerve and induce rapid activation of parasympathetic brainstem regions, which then leads to the release of acetylcholine from efferent vagus nerve fibres and resultant negative-feedback control of inflammation.34 The primary effector neurotransmitter of the parasympathetic nervous system is acetylcholine, which binds to two general receptor subtypes, nicotinic and muscarinic cholinergic receptors. Both receptors are found in immune cells, but nicotinic receptors specifically mediate choli nergic anti -i nf lamm atory ef f ects i n macrophages. 35 Activation of this receptor on macrophages inhibits NF-κB signaling, thereby repressing proinflammatory cytokine production.35 A recent report also indicates that nicotine, a cholinergic agonist, inhibits macrophage cytokine production by recruiting JAK2 (Janus kinase 2) to the α7 subunit. This initiates the anti-inflammatory STAT3 (signal transducer and activator of transcription 3) and SOCS3 (suppressor of cytokine signaling 3) signaling cascades. The cholinergic neuronal inflammatory reflex pathway also prevents increased serum concentrations of TNF during toxic shock, through the release of acetylcholine from the vagus nerve, indicating that this pathway plays an important role in preventing excessive inflammatory responses. Accordingly, vagotomy exacerbates the TNF response to inflammatory stimuli and sensitizes animals to the lethal effects of endotoxin, whereas cholinergic agonists and vagus-nerve stimulation prevent these effects.34 Acetylcholine also inhibits endotoxin-induced release of pro-inflammatory cytokines (IL-1, IL-6 and TNF) but not anti-inflammatory cytokines (IL-10) from macrophages.35 Additional support for a role for the parasympathetic nervous system in dampening inflammatory responses is provided by acetylcholine-mediated inhibition of high mobility group box 1 (HMGB1), a protein released by activated macrophages during severe sepsis. Therefore, as for glucocorticoid and SNS regulation of innate immunity, the parasympathetic nervous system is activated by cytokines released during acti-

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vation of the innate immune system, and in turn provides a negative feedback control of innate immune responses to restore homeostasis. There are some controversies in the literature regarding the cellular source of acetylcholine that regulates inflammation. It has been suggested that the source of acetylcholine acting on macrophages is more likely to be immune-cell derived than released from nerve endings.36 Regulation of immune system on neuroendocrine responses It has been demonstrated that there is a bidirectional communication between nervous and immune systems. There is considerable evidence that the peripheral immune system can signal the brain to elicit neuroendocrine response through immune mediators and cytokines. The peripheral immune molecules influence neuroendocrine responses through various mechanisms, including cytokine’s direct entry into the brain as well as stimulation of afferent neurons of the vagus nerve. 37 Regarding to the passage of cytokines across the blood brain barrier, there are at least two pathways. One of them is through fenestrated capillaries in different regions of the CNS. These sites are relatively devoid of a blood-brain barrier such as the structures lining the anteroventral border of the third ventricle and the posterior lobe of the pituitary. Their capillaries do not form tight junctions and are thus far more readily penetrable via the paracellular route.38 Another possibility is increased permeability of the blood-brain barrier after trauma, which enhances the access of peripheral immune cells or their products to the CNS. 39 The mechanisms involved in the interaction between peripheral cytokines and vagal fibers are still under investigation. The localized perivagal cytokine production may contribute to this signaling mechanism.40 This afferent signaling pathway to the CNS in response to peripheral inflammatory challenges functions as a feedback mechanism. This bidirectional neuroimmune interaction creates a circuit of responses that can be considered as an inflammatory reflex. The integrity of such circuit is critical in host protection and adaptation to systemic challenges such as traumatic injury and infection. Conclusion To control inflammation during a period after injury is essential for tissue repair and maintenance of immune competence. The initiation and termination of the

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inflammatory response is under neuroendocrine control through direct neurotransmitter release at the target organ, as well as indirect action through humoral factors, including catecholamines, neuropeptides, and glucocorticoids. Although the early post-traumatic inflammatory response is directed to repair tissues and establish immune competence, an increased magnitude and duration of this response is associated with delayed restoration of homeostasis and increases tissue injury leading to multiple organ failure. The neuroendocrine responses have been demonstrated to exert direct effects on cells of the immune system, affecting cytokine expression, lymphocyte function, and cytotoxic activity. In turn, the inflammatory mediators released communicate with the CNS through stimulation of sensory and vagal afferents or by crossing the bloodbrain barrier through active transport mechanisms or by taking advantage of areas with fenestrated capillaries. This neuroendocrine-immune feedback loop is pivotal to maintenance of immune homeostasis in trauma. Neuroendocrine response might have varying effects on immune system, enhancing or dampening, which might be dependent on the magnitude of neuroendocrine responses, presence of immune challenge, type of immune cells, and so on.

tem and the CNS that occur at systemic, regional and local levels, and will provide further evidence that these interactions have important physiological roles in health and disease.

REFERENCES 1. Jiang JX, Shu YP, Huang YS, et al. Current basic research in systemic insults at the early stage of trauma and its prospect. Chin J Traumatol 2002;18(4):197-199. 2. Sheridan JF, Padgett DA, Avitsur R, et al. Experimental models of stress and wound healing. World J Surg 2004; 28(3): 327-330. 3. Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 2006; 6(4):318-328. 4. Molina PE. Neurobiology of the stress response: contribution of the sympathetic nervous system to the neuroimmune axis in traumatic injury. Shock 2005;24(1):3-10. 5. Kariagina A, Romanenko D, Ren SG. Hypothalamic-pituitary cytokine network. Endocrinology 2004;145(1):104-112. 6. Derijk R, Michelson D, Karp B, et al. Exercise and circadian rhythm induced variations in plasma cortisol differentially regulate interleukin-1 β(IL-1 β), IL-6, and tumour necrosis factor- α(TNF- α) production in humans: high sensitivity of TNFα and resistance of IL-6. J Clin Endocrinol Metab 1997;82(7):

For many years, the concept that the central and peripheral nervous systems regulate immunity is considered to be highly controversial. However, as described in this review, a wealth of data has now been accumulated, indicating that the molecular machinery required to respond to neurotransmitters, neuropeptides and neurohormones are indeed present in immune cells. In addition, in some cases, immune cells produce and secrete neural mediators, supporting the importance of such mechanisms of immune regulation. However, the precise cellular source and maturation phase at which immune cells either produce such molecules or respond to them still requires clarification. In addition, the signalling mechanisms and physiological circumstances under which such regulation occurs largely remain unaddressed. And with most studies so far focusing on the effects of glucocorticoids on innate immune responses, evidence for a role of other neuropeptides and neurotransmitters in innate recognition systems, such as TLRs on immune cells, is scarce. Research that focuses on these issues should provide further important insights into the molecular mechanisms and physiological role of the links between the immune sys-

2182-2191. 7. Singh A, Zelazowska EB, Petrides JS, et al. Lymphocyte subset responses to exercise and glucocorticoid suppression in healthy men. Med Sci Sports Exerc 1996;28(7):822-828. 8. Matyszak MK, Citterio S, Rescigno M, et al. Differential effects of corticosteroids during different stages of dendritic cell maturation. Eur J Immunol 2000;30(4):1233-1242. 9. Moser M, De Smedt T, Sornasse T, et al. Glucocorticoids down-regulate dendritic cell function in vitro and in vivo. Eur J Immunol 1995;25(10):2818-2824. 10. Sacedon R, Vicente A, Varas A, et al. Early differentiation of thymic dendritic cells in the absence of glucocorticoids. J Neuroimmunol 1999;94(1-2): 103-108. 11. Ma W, Gee K, Lim W, et al. Dexamethasone inhibits IL12p40 production in lipopolysaccharide-stimulated human monocytic cells by down-regulating the activity of c-Jun N-terminal kinase, the activation protein-1, and NF- κB transcription factors. J Immunol 2004;172(1): 318-330. 12. Agarwal SK, Marshall GD Jr. Dexamethasone promotes type 2 cytokine production primarily through inhibition of type 1 cytokines. J Interferon Cytokine Res 2001;21(3):147-155. 13. Atsuta J, Plitt J, Bochner BS, et al. Inhibition of VCAM-1 expression in human bronchial epithelial cells by glucocorticoids.

. 208 .

Am J Respir Cell Mol Biol 1999;20(4):643-650.

Chinese Journal of Traumatology 2008; 11(4):203-208

27. van der Poll T, Coyle SM, Barbosa K, et al. Epinephrine

14. Pitzalis C, Piptone N, Bajocchi G, et al. Corticosteroids

inhibits tumor necrosis factor- α and potentiates interleukin 10

inhibit lymphocyte binding to endothelium and intercellular

production during human endotoxemia. J Clin Invest 1996; 97(3):

adhesion: an additional mechanism for their anti-inflammatory and

713-719.

immunosuppressive effect. J Immunol 1997;158(10):5007-5016.

28. Lang K, Drell TL, Niggemann B, et al. Neurotransmitters

15. Richards DF, Fernandez M, Caulfield J, et al. Glucocorti-

regulate the migration and cytotoxicity in natural killer cells.

coids drive human CD8(+)T cell differentiation towards a phenotype with high IL-10 and reduced IL-4, IL-5 and IL-13 production. Eur J Immunol 2000;30(8): 2344-2354. 16. Pype JL, Dupont LJ, Menten P, et al. Expression of monocyte chemotactic protein (MCP)-1, MCP-2, and MCP-3 by hu-

Immunol Lett 2003;90(2-3):165-172. 29. Maestroni GJ. Short exposure of maturing, bone marrowderived dendritic cells to norepinephrine: impact on kinetics of cytokine production and Th development. J Neuroimmunol 2002; 129(1-2):106-114.

man airway smooth-muscle cells. Modulation by corticosteroids

30. Molina PE. Noradrenergic inhibition of TNF upregulation

and T-helper 2 cytokines. Am J Respir Cell Mol Biol 1999;21(4):

in hemorrhagic shock. Neuroimmunomodulation 2001;9(3):125-133.

528-536. 17. Zhou JY, Jiang JX, Yang C, et al. Effect of corticosterone on peritoneal macrophages in rats. Acta Acad Med Milit Tertiae 2008;30(2):120-123. 18. Dhabhar FS. Stress-induced enhancement of cell-mediated immunity. Ann N Y Acad Sci 1998;840:359-372.

31. Johnson JD, Campisi J, Sharkey CM, et al. Adrenergic receptors mediate stress-induced elevations in extracellular Hsp72. J Appl Physiol 2005;99(5):1789-1795. 32. Madden KS, Sanders VM, Felten DL. Catecholamine influences and sympathetic neural modulation of immune responsiveness. Annu Rev Pharmacol Toxicol 1995;35:417-448.

19. Smyth GP, Stapleton PP, Freeman TA, et al. Glucocorti-

33. Zhou M, Yang S, Koo DJ, et al. The role of Kupffer cell a-

coid pretreatment induces cytokine overexpression and nuclear fac-

adrenoceptors in norepinephrine-induced TNF- α production.

tor- κB activation in macrophages. J Surg Res 2004;116(2): 253-

Biochim Biophys Acta 2001;1537(1):49-57.

261. 20. Edwards CK 3rd, Yunger LM, Lorence RM, et al. The

34. Tracey KJ. The inflammatory reflex. Nature 2002;420 (6917):853-859.

pituitary gland is required for protection against lethal effects of

35. Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine

Salmonella typhimurium. Proc Natl Acad Sci USA 1991;88(6):

receptor α7 subunit is an essential regulator of inflammation.

2274-2277.

Nature 2003;421(6921):384-388.

21. Ruzek MC, Pearce BD, Miller AH, et al. Endogenous

36. Kawashima K, Fujii T. Expression of non-neuronal ace-

glucocorticoids protect against cytokine-mediated lethality during

tylcholine in lymphocytes and its contribution to the regulation of

viral infection. J Immunol 1999; 162(6): 3527-3533.

immune function. Front Biosci 2004;9:2063-2085.

22. Gomez SA, Fernandez GC, Vanzulli S, et al. Endogenous

37. Goehler LE, Gaykema RP, Hansen MK, et al. Vagal im-

glucocorticoids attenuate Shiga toxin-2-induced toxicity in a mouse

mune-to-brain communication: a visceral chemosensory pathway.

model of haemolytic uraemic syndrome. Clin Exp Immunol 2003;

Auton Neurosci 2000;85(1-3):49-59.

131(2):217-224. 23. MacPhee IA, Antoni FA, Mason DW. Spontaneous recovery of rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids. J Exp Med 1989;169(2):431-445. 24. Severn A, Rapson NT, Hunter CA, et al. Regulation of tumor necrosis factor production by adrenaline and beta-adrenergic agonists. J Immunol 1992;148(11):3441-3445. 25. Hasko G, Szabo C, Nemeth ZH, et al. Dopamine suppresses IL-12 p40 production by lipopolysaccharide-stimulated

38. Rivest S. How circulating cytokines trigger the neural circuits that control the hypothalamic-pituitary-adrenal axis. Psychoneuroendocrinology 2001;26(8):761-788. 39. Brown KA. Factors modifying the migration of lymphocytes across the blood-brain barrier. Int Immunopharmacol 2001; 1(2):2043-2062. 40. Goehler LE, Gaykema RP, Nguyen KT, et al. Interleukin-1 beta in immune cells of the abdominal vagus nerve: a link between the immune and nervous systems? J Neurosci 1999;19(7):27992806.

macrophages via a β-adrenoceptor-mediated mechanism. J Neuroimmunol 2002;122:34-39. 26. Hasko G, Shanley TP, Egnaczyk G, et al. Exogenous and endogenous catecholamines inhibit the production of macrophage inflammatory protein (MIP) 1 α via a β-adrenoceptor-mediated mechanism. Br J Pharmacol 1998;125(6):1297-1303.

(Received May 17, 2008 ) Edited by LIU Jun-lan