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Neuroimmune Peptides
Chapter 92
Neuroimmune Peptides Ning Zhang, Hua Geng and Joost J. Oppenheim
ABSTRACT Increasing evidence has shown that many neuropeptides modulate immune responses in addition to their well-documented function in the central and peripheral nervous systems. Surprisingly, RT-PCR, Western blotting, and functional assays reveal the production of these neuropeptides by the immune system and the expression of their receptors on leukocyte surface. This chapter will provide a brief summary of the immunological activities of neuropeptides.
INTRODUCTION The nervous and immune systems are tightly integrated and orchestrated to serve the complicated tasks of host sensation and response. A disturbance in one system often has a profound effect on the other. For example, activation of the hypothalamic–pituitary–adrenal (HPA) axis by long-term stress often elicits suppression of both innate and adaptive immunities.6 Conversely, inflammatory immune responses activate central nervous system sensory pain pathways.34,35 Increasing evidence suggests that a family of immunoactive neuropeptides provides key signals between these two systems. Beyond their well-characterized effects in the nervous system, these neuropeptides also interact with their receptors on leukocytes, thus modulating the function of these pivotal mediators of host defense. Further, leukocytes are also capable of producing many of these peptides in the peripheral immune system. The structure, properties, and roles of neuropeptides in the central and peripheral nervous systems are discussed in other chapters of this book. This section will briefly describe the immunological effects of these neuropeptides as summarized in Table 1. Other actions of these peptides are discussed elsewhere in this book. Neuropeptides influence host immune defenses based on two mechanisms. First, these peptides indirectly regulate the immune response by acting on the different axis of the central nervous system. For example, Met-enkephalin, an endogenous opioid, stimulates the HPA-axis-mediated production of corticosterone, a potent immunosuppressive hormone.19 Opioids also activate the sympathetic nervous Handbook of Biologically Active Peptides. http://dx.doi.org/10.1016/B978-0-12-385095-9.00092-0 Published by Elsevier Inc.
system, resulting in an increase in the level of circulating epinephrine from the adrenal medulla and secretion of the norepinephrine by sympathetic nerve terminals. Increased catecholamine levels have been linked to the suppression of natural killer cell and lymphocyte function. Second, all the peptides listed in Table 1 are able to directly regulate the functions of receptor expressing leukocytes, independent of their neuronal activities. Studies using reverse transcription-polymerase chain reaction (RT-PCR) or western blotting analysis reveal the expression of a wide variety of neuropeptide receptors on various types of leukocytes. For example, all three subtypes of opioid receptors, µ-, δ-, and κ-receptors, have been detected on T cell, B cells, monocytes, neutrophils, and natural killer cells.23 Stimulation of these neuropeptide receptors can modulate leukocyte production of proinflammatory cytokines. Interestingly, most neuropeptide receptors are seven-transmembrane domaincontaining receptors, which exert their function by activating heterotrimeric G proteins. Neuropeptides are mainly expressed and active in the central and peripheral nervous systems. However, these peptides can also be unexpectedly produced and are functional in other peripheral tissues. For example, adrenocorticotropic hormone/corticotropin (ACTH) is not only produced by pituitary cells but also to a limited extent by leukocytes.2 Endogenous opioids are expressed by leukocytes and play an important role in peripheral analgesic effects.29 In addition to being produced in the pituitary gland, α-melanocytestimulating hormones (αMSH) are also highly expressed in the skin and the gastro intestinal (GI) tract cells.21 Substance P mRNA and protein have been detected in the thymic medulla and purified CD5+ thymocytes.27 The neuropeptides of the HPA axis play a profound role in inflammation. Stressful stimuli activate the HPA axis through the release of a sequential series of neuropeptide hormones, beginning with the production of hypothalamic corticotropin-releasing hormone (CRH) and followed by pituitary derived ACTH, culminating in the secretion of glucocorticoids, potent anti-inflammatory hormones produced by the adrenal cortex.6 Vasopressin (AVP) potentiates 681
682
TABLE 1 Neuropeptides Regulating Receptor Expressing Leukocytes Size
Receptors in immune system
Immune effects
Nonimmune effects
CRH
41aa
Neutrophils, eosinophils, thymus, spleen
Enhances the production of immunosuppresive glucocorticoids through the HPA axis, enhances peripheral inflammation. Urocortin (Ucn), UcnI, and UcnII share similar properties.
Endocrine-signaling peptide involved in the stress response
Urocortin (Ucn)
40aa
Monocytes, macrophages, dendritic cells, polymorphonuclear cells, T cells
Inhibits inflammatory cytokines and chemokines production, T cell proliferation, and TH1 response; enhances IL-10/transforming growth factor (TGF)-β1 production; induces regulatory T cells.
Regulates vasodilatation, bronchodilatation, cardiac output, smooth muscle relaxation, food intake, and ACTH secretion.
Somatostatin
14aa, or 28aa
T cells, monocytes
Inhibits the secretion of proinflammatory cytokines and antibodies by immune cells; inhibits lymphocyte proliferation.
Inhibits secretion of numerous growth hormones.
Cortistatin
17aa
Monocytes, macrophages, dendritic cells, T cells
Inhibits inflammatory cytokines and chemokines production, T cell proliferation, and TH1 response; induces regulatory T cells.
Inhibits locomotor activity, regulates growth hormone.
Vasopressin (AVP)
9aa
T cells, B cells, monocytes
Enhances production of immunosuppresive glucocorticoids through the HPA axis, enhances secretion of IFN-γ by T-cells.
Potentiates CRH effects, responds to osmotic and hemodynamic stress.
Gastrin-releasing peptides (GRP)
27aa
Macrophage, T cells, natural killer cells
Stimulates phagocytic activities of macrophages, inhibits Con-A induced proliferation of lymphocytes. Bombesin and neuromedin C share similar properties.
Activates the sympathetic nervous system to modulate stress, fear, and anxiety responses.
Met-enkephalin and endorphins
5aa
T cell, B cells monocytes, neutrophils, natural killer cells
Induces heterologous desensitization of chemokine receptors, inhibits natural killer cell activity, suppresses IL2 and IFNγ production.
Analgesic peptides, induces the secretion of corticosterone.
ACTH
39aa
T helper cells, B cells, macrophages
Enhances production of immunosuppresive glucocorticoids through the HPA axis.
Endocrine-signaling peptides involved in the response to stress.
αMSH (melanocortin)
13aa
Monocytes, macrophages, natural killer cells, T helper cells, B cells, and dendritic cells
Downregulates the production of proinflammatory cytokines, downregulates the expression of costimulatory molecules (CD86, CD40, ICAM-1) on antigen-presenting dendritic cells, upregulates IL-10. inhibits cutaneous inflammation, inhibits T cell proliferation, and induces regulatory T cells.
Regulation of energy homeostasis.
Chapter | 92 Neuroimmune Peptides
Neuropeptides
36aa
Monocytes, T cells, B cells, natural killer cells
Elicits neurogenic inflammation by inducing the secretion of substance P, contributes to colitis, potentiates paw edema; enhances T cell adhesion to fibronectin; increases release of oxidative reagents by neutrophils, suppresses NK cell activity; enhances phagocytosis by monocyte.
Regulates energy balance, food intake, and antihyperalgesia, antimicrobial peptide, affects skin color, antipyretic effects.
VIP/PACAP
28aa
T cells, mast cells, macrophages, monocytes, dentritic cells, polymorphonuclear cells
Inhibits leukocyte recruitment, cytokine production; polarizes TH2 responses, induces T lymphocyte adhesion and chemotaxis, inhibits TH1 response and recruitment, enhances tolerogenic DC generation. PACAP possesses similar anti-inflammatory activities.
Neurotransmitter, secretagogue, neuroprotective, neurotrophic, and vasodilator.
Substance P (neurokinin1, tachykinin 1)
11aa
T cells, macrophages, dendritic cells
Contributes to neurogenic inflammation, involves in various respiratory diseases and pancreatitis. Substance K (neurokinin A) possesses similar proinflammatory activities.
Induces hyperalgesia
CGRP
37aa
T cells, B cells, dendritic cells
Contributes to neurogenic inflammation, involves in various aspiratory diseases.
Induces vasodilatation
Bradykinin
9aa
Monocytes, neutrophils, eosinophils, T cells
Induces chemotaxis of neutrophils, Induces hyperalgesia; vasodilator. stimulates the secretion of superoxide radicals, exacerbates infection, contributes to ischemia reperfusion, involved in respiratory diseases.
Adrenomedullin (AM)
52aa
Monocytes, macrophages
Inhibits inflammatory cytokines and chemokine production, T cell proliferation, and TH1 response; induces regulatory T cells; Stimulates IL-10/TGF-β production.
Regulates vasodilatation, bronchodilatation, cardiac output, and smooth muscle relaxation.
Ghrelin
28aa
Monocytes, macrophages, dendritic cells, T cells
Inhibits inflammatory cytokines and chemokine production; suppresses T cell proliferation, and TH1 response (IL-2 and IFN-γ production); induces regulatory T cells
Regulates cardiac output, appetite, adiposity, vasodilatation; enhances GI secretion, and gastric motility.
SECTION | IX Handbook of Biologically Active Peptides: Immune/Inflammatory Peptides
Neuropeptide Y
CRH: corticotropin-releasing hormone; αMSH: alpha-melanocyte-stimulating hormone; ACTH: adrenocorticotropic hormone/corticotropin; CGRP: calcitonin-gene-related peptide; VIP: vasoactive intestinal polypeptide.
683
684
the capacity of CRH to activate the HPA axis. The resultant elevated glucocorticoid concentrations in the circulation contribute to stress-induced immunosuppression. Surprisingly, CRH and AVP are also produced by leukocytes, and their receptors are expressed by leukocytes. Although hypothalamic CRH and AVP have indirect anti-inflammatory effects through the stimulation of glucocorticoids, these peptides seem to have direct proinflammatory effects in the peripheral tissues. AVP stimulates the secretion of interferon-γ by T-lymphocytes.18 CRH elicits the production of interleukin (IL)-1 by human monocytes and enhances mouse natural killer (NK) cell activity.5 CRH and its family members, urocortin (Ucn), UcnI, and UcnII have been shown to exacerbate symptoms of experimental autoimmune encephalomyelitis and toxin A-induced inflammatory diarrhea.1 The expression of Ucn is upregulated during inflammation.17 Ucn induces apoptosis of macrophage during inflammation, suggesting its important anti-inflammatory effect.31 Regarding innate immunity, Ucn inhibits the production of several proinflammatory cytokines, such as tumor necrosis factor (TNF)α, IL-6, and IL-12, and further in vivo disease-associated (i.e. sepsis and inflammatory bowel disease) studies support the anti-inflammatory role of Ucn.14 Thus, their antagonists have been tested as therapeutics for arthritis and preliminary results are encouraging.33 Inflammation induces hyperalgesia. This is in part attributable to the chemokine receptor-induced desensitization of analgesic opioid receptors and concomitant sensitization of algesic vanilloid receptors transient receptor potential vanilloid (TRPV)1 on neurons.34,35 Conversely, opioid receptors on leukocytes have immunosuppressive effects. Met-enkephalin, an endogenous opioid, is an analgesic peptide of 5 amino acids.3 It exerts immunosuppressive effects by heterologous desensitization of chemokine receptors and enhancing the secretion of corticosteroids.23 TRPV1 is also expressed by leukocytes, but its immune function remains unknown. Painful stimuli activate peripheral neurons to release several immunostimulatory peptides, including substance P and calcitonin-gene-related peptide (CGRP). These peptides have proinflammatory effects and are associated with neurogenic inflammation. Substance P, a hyperalgesic peptide, belongs to the tachykinin family. It stimulates the influx of neutrophils and eosinophils into the human dermis, induces the secretion of TNFα by macrophages, and it enhances leukocyte adhesion to endothelial cells, which may contribute to its proinflammatory effects in various respiratory diseases, pancreatitis, and inflammatory bowel disease.24 Substance K, another peptide in the tachykinin family, possesses similar proinflammatory effects. CGRP is also involved in neurogenic respiratory diseases such as asthma, chronic obstructive pulmonary disease, or chronic cough.28 Adrenomedullin (AM) could function as an endogenous
Chapter | 92 Neuroimmune Peptides
anti-inflammatory immune modulator with a high structural homology to CGRP.11 Unlike CGRP, AM could effectively prevent arthritis and sepsis through inhibiting the inflammatory response in these autoimmune/inflammatory diseases.12,14 Neuropeptide Y (NPY), a key peptide regulating energy balance and food intake in central nervous system (CNS), also induces the secretion of substance P by peripheral neurons, contributing to colitis and paw edema in animal models of inflammation.10 Further, NPY directly enhances T cell adhesion to fibronectin20 and plays a major role in the regulation of Th1 responses.26 Bradykinin, another hyperalgesic peptide, facilitates septic shock, exacerbates ischemia reperfusion, and enhances airway inflammation based on its vasodilatory effects.4 There several other neuropeptides that downregulate immune responses. Vasoactive intestinal polypeptide (VIP) has immunosuppressive effects based on its capacity to inhibit leukocyte recruitment to inflammatory sites. VIP also induces polarization to the T helper (TH)2 type of antibody-based allergic responses.25 In addition, VIP induces the differentiation of tolerogenic dentritic cells that promote generation of antigen specific Treg cells.15 αMSH downregulates the production of proinflammatory cytokines, inhibits the expression of costimulatory molecules (CD86, CD40, and intercellular adhesion molecule (ICAM)-1) on dendritic cells, and upregulates IL-10, resulting in immunosuppression.22 An increasing body of evidence shows that VIP and αMSH could regulate TH1/TH2/Treg immune homeostasis and induce immune tolerance and inhibit autoimmune response through inhibiting the production of inflammatory cytokines and chemokines, polarizing the differentiation of T cells toward TH2 or Treg, and suppressing the activation of autoreactive T cells by IL-10 and TGFβ.11,13 Moreover, both VIP and αMSH inhibit phagocytic activity as well as the migration and adherence of macrophages and neutrophils.9 Ghrelin is one of the anti-inflammatory neuropeptides with an immunomodulatory role through binding to its receptor growth hormone secretagog receptor (GHSR), and subsequently activating the cyclic adenosine monophosphate-protein kinase A signaling pathway that is associated with anti-inflammatory actions.13 Somatostatin inhibits the secretion of interferons (IFN)-γ and cerebrospinal fluid, enhances the secretion of IL-10 and IL-4, downregulates the secretion of antibodies by B lymphocytes, and impairs lymphocyte proliferation.30 Cortistatin has a strong structural similarity to somatostatin. Cortistatin is expressed in various immune cells, including monocytes, macrophages, lymphocytes, and dentritic cells, with its expression upregulated on cell differentiation and activation, suggesting that cortistatin may act as a major immune regulator.11 In addition, both in vitro and in vivo studies show that cortistatin functions more efficiently than somatostatin in its antiinflammatory responses, probably because of the capacity
SECTION | IX Handbook of Biologically Active Peptides: Immune/Inflammatory Peptides
of cortistatin to activate different receptors and signaling pathways.7,16 Cortistatin cannot only bind to somatostatin receptor subtypes (SSTs), but also to GHSR, thus leading to the activation of both cAMP-independent (SST mediated) and -dependent (GHSR-mediated) signaling.13,32 Gastrinreleasing peptide (GRP) and neuromedin C belong to the bombesin peptide family. They stimulate phagocytic activities of macrophages but inhibit concanavalin-A induced proliferation of lymphocytes.8 In summary, increasing evidence has confirmed the production of neuropeptides and the expression of their receptors by cells of the immune system. Further, neuropeptides directly contribute to a wide range of diseases, such as stress-induced immunosuppresion, asthma, and inflammatory bowel disease. However, many more studies are needed to connect in vitro observations, based on the use of isolated leukocytes, to the in vivo systemic effects of neuropeptides in disease. Further, it is critical to understand that the anatomical and temporal distribution of these peptides may determine their overall effects on immune responses. For example, CRH acts as an anti-inflammatory agent when it exerts its effects in the CNS to stimulate the production of ACTH and then glucocorticoids. However, in the peripheral tissues, CRH is proinflammatory, and its antagonists can be used to treat arthritis in animal models. Experiments from various animal models with knockout of VIP, AM, VIP/ PACAP receptors, or Ucn result in endotoxemia and lung inflammation as well as Th1-mediated responses in vivo, and further highlight the physiological relevance of these neuroimmune peptides in certain inflammatory and autoimmune conditions. In summary, a broad range of neuropeptides is capable of influencing immune responses. They may serve to integrate a host’s immune and nervous system response to injurious environmental stimuli. The physiological relevance of immunoregulatory activity of these neuropeptides needs further investigation.
ACKNOWLEDGMENTS The authors thank Dr. Esther M. Sternberg for reviewing the manuscript and constructive discussion. This research was supported [in part or whole] by the Intramural Research Program of the National Institute Health (NIH), National Cancer Institute.
REFERENCES 1. Anton PM, Gay J, Mykoniatis A, Pan A, O’Brien M, Brown D, et al. Corticotropin-releasing hormone (CRH) requirement in Clostridium difficile toxin A-mediated intestinal inflammation. Proc Natl Acad Sci U S A 2004;101:8503–8. 2. Blalock JE. Production of peptide hormones and neurotransmitters by the immune system. Chem Immunol 1992;52:1–24. 3. Bodnar RJ, Klein GE. Endogenous opiates and behavior. Peptides 2003;2004(25):2205–56.
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4. Calixto JB, Medeiros R, Fernandes ES, Ferreira J, Cabrini DA, Campos MM. Kinin B1 receptors: key G-protein-coupled receptors and their role in inflammatory and painful processes. Br J Pharmacol 2004;143:803–18. 5. Carr DJ, DeCosta BR, Jacobson AE, Rice KC, Blalock JE. Corticotropin-releasing hormone augments natural killer cell activity through a naloxone-sensitive pathway. J Neuroimmunol 1990;28: 53–61. 6. Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol 2005;67:259–84. 7. Deghenghi R, Papotti M, Ghigo E, Muccioli G. Cortistatin, but not somatostatin, binds to growth hormone secretagogue (GHS) receptors of human pituitary gland. J Endocrinol Invest 2001;24: RC1–3. 8. Del Rio M, Hernanz A, de la Fuente M. Bombesin, gastrin-releasing peptide, and neuromedin C modulate murine lymphocyte proliferation through adherent accessory cells and activate protein kinase C. Peptides 1994;15:15–22. 9. Delgado M, Pozo D, Ganea D. The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev 2004;56: 249–90. 10. Dimitrijevic M, Stanojevic S, Vujic V, Kovacevic-Jovanovic V, Beck-Sickinger A, Demuth H, et al. Effect of neuropeptide Y on inflammatory paw edema in the rat: involvement of peripheral NPY Y1 and Y5 receptors and interaction with dipeptidyl-peptidase IV (CD26). J Neuroimmunol 2002;129:35–42. 11. Gonzalez-Rey E, Chorny A, Delgado M. Regulation of immune tolerance by anti-inflammatory neuropeptides. Nat Reviews Immunol 2007;7:52–63. 12. Gonzalez-Rey E, Chorny A, O’Valle F, Delgado M. Adrenomedullin protects from experimental arthritis by down-regulating inflammation and Th1 response and inducing regulatory T cells. Am J Pathol 2007;170:263–71. 13. Gonzalez-Rey E, Delgado M. Anti-inflammatory neuropeptide receptors: new therapeutic targets for immune disorders? Trends Pharmacol Sci 2007;28:482–91. 14. Gonzalez-Rey E, Fernandez-Martin A, Chorny A, Delgado M. Therapeutic effect of urocortin and adrenomedullin in a murine model of Crohn’s disease. Gut 2006;55:824–32. 15. Gonzalez-Rey E, Ganea D, Delgado M. Neuropeptides: keeping the balance between pathogen immunity and immune tolerance. Curr Opin Pharmacol 2010;10:473–81. 16. Gonzalez-Rey E, Varela N, Sheibanie AF, Chorny A, Ganea D, Delgado M. Cortistatin, an antiinflammatory peptide with therapeutic action in inflammatory bowel disease. Proc Natl Acad Sci U S A 2006;103:4228–33. 17. Gravanis A, Margioris AN. The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications. Curr Med Chem 2005;12:1503–12. 18. Johnson HM, Torres BA. A novel arginine vasopressin-binding peptide that blocks arginine vasopressin modulation of immune function. J Immunol 1988;141:2420–3. 19. Law PY, Wong YH, Loh HH. Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol 2000;40: 389–430. 20. Levite M, Cahalon L, Hershkoviz R, Steinman L, Lider O. Neuropeptides, via specific receptors, regulate T cell adhesion to fibronectin. J Immunol 1998;160:993–1000.
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21. Loir B, Bouchard B, Morandini R, Del Marmol V, Deraemaecker R, Garcia-Borron JC, et al. Immunoreactive alpha-melanotropin as an autocrine effector in human melanoma cells. Eur J Biochem 1997; 244:923–30. 22. Luger TA, Scholzen TE, Brzoska T, Bohm M. New insights into the functions of alpha-MSH and related peptides in the immune system. Ann N Y Acad Sci 2003;994:133–40. 23. McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ. Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 2001;62:111–23. 24. O’Connor TM, O’Connell J, O’Brien DI, Goode T, Bredin CP, Shanahan F. The role of substance P in inflammatory disease. J Cell Physiol 2004;201:167–80. 25. Pozo D, Delgado M. The many faces of VIP in neuroimmunology: a cytokine rather a neuropeptide? FASEB J 2004;18:1325–34. 26. Prod’homme T, Weber MS, Steinman L, Zamvil SS. A neuropeptide in immune-mediated inflammation, Y? Trends Immunol 2006;27:164–7. 27. Santoni G, Amantini C, Lucciarini R, Pompei P, Perfumi M, Nabissi M, et al. Expression of substance P and its neurokinin-1 receptor on thymocytes: functional relevance in the regulation of thymocyte apoptosis and proliferation. Neuroimmunomodulation 2002;10:232–46. 28. Springer J, Geppetti P, Fischer A, Groneberg DA. Calcitonin generelated peptide as inflammatory mediator. Pulm Pharmacol Ther 2003;16:121–30.
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29. Stein C, Schafer M, Machelska H. Attacking pain at its source: new perspectives on opioids. Nat Med 2003;9:1003–8. 30. ten Bokum AM, Hofland LJ, van Hagen PM. Somatostatin and somatostatin receptors in the immune system: a review. Eur Cytokine Netw 2000;11:161–76. 31. Tsatsanis C, Androulidaki A, Dermitzaki E, Charalampopoulos I, Spiess J, Gravanis A, et al. Urocortin 1 and urocortin 2 induce macrophage apoptosis via CRFR2. FEBS Lett 2005;579:4259–64. 32. Varela N, Chorny A, Gonzalez-Rey E, Delgado M. Tuning inflammation with anti-inflammatory neuropeptides. Expert Opin Biol Ther 2007;7:461–78. 33. Webster EL, Barrientos RM, Contoreggi C, Isaac MG, Ligier S, Gabry KE, et al. Corticotropin releasing hormone (CRH) antagonist attenuates adjuvant induced arthritis: role of CRH in peripheral inflammation. J Rheumatol 2002;29:1252–61. 34. Zhang N, Inan S, Cowan A, Sun R, Wang JM, Rogers TJ, et al. A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1. Proc Natl Acad Sci U S A 2005;102: 4536–41. 35. Zhang N, Rogers TJ, Caterina M, Oppenheim JJ. Proinflammatory chemokines, such as C-C chemokine ligand 3, desensitize muopioid receptors on dorsal root ganglia neurons. J Immunol 2004;173: 594–9.
Neuroimmune Peptides Ning Zhang, Hua Geng and Joost J. Oppenheim
ABSTRACT Increasing evidence has shown that many neuropeptides modulate immune responses in addition to their well-documented function in the central and peripheral nervous systems. Surprisingly, RT-PCR, Western blotting, and functional assays reveal the production of these neuropeptides by the immune system and the expression of their receptors on leukocyte surface. This chapter will provide a brief summary of the immunological activities of neuropeptides.
INTRODUCTION The nervous and immune systems are tightly integrated and orchestrated to serve the complicated tasks of host sensation and response. A disturbance in one system often has a profound effect on the other. For example, activation of the hypothalamic–pituitary–adrenal (HPA) axis by long-term stress often elicits suppression of both innate and adaptive immunities.6 Conversely, inflammatory immune responses activate central nervous system sensory pain pathways.34,35 Increasing evidence suggests that a family of immunoactive neuropeptides provides key signals between these two systems. Beyond their well-characterized effects in the nervous system, these neuropeptides also interact with their receptors on leukocytes, thus modulating the function of these pivotal mediators of host defense. Further, leukocytes are also capable of producing many of these peptides in the peripheral immune system. The structure, properties, and roles of neuropeptides in the central and peripheral nervous systems are discussed in other chapters of this book. This section will briefly describe the immunological effects of these neuropeptides as summarized in Table 1. Other actions of these peptides are discussed elsewhere in this book. Neuropeptides influence host immune defenses based on two mechanisms. First, these peptides indirectly regulate the immune response by acting on the different axis of the central nervous system. For example, Met-enkephalin, an endogenous opioid, stimulates the HPA-axis-mediated production of corticosterone, a potent immunosuppressive hormone.19 Opioids also activate the sympathetic nervous Handbook of Biologically Active Peptides. http://dx.doi.org/10.1016/B978-0-12-385095-9.00092-0 Published by Elsevier Inc.
system, resulting in an increase in the level of circulating epinephrine from the adrenal medulla and secretion of the norepinephrine by sympathetic nerve terminals. Increased catecholamine levels have been linked to the suppression of natural killer cell and lymphocyte function. Second, all the peptides listed in Table 1 are able to directly regulate the functions of receptor expressing leukocytes, independent of their neuronal activities. Studies using reverse transcription-polymerase chain reaction (RT-PCR) or western blotting analysis reveal the expression of a wide variety of neuropeptide receptors on various types of leukocytes. For example, all three subtypes of opioid receptors, µ-, δ-, and κ-receptors, have been detected on T cell, B cells, monocytes, neutrophils, and natural killer cells.23 Stimulation of these neuropeptide receptors can modulate leukocyte production of proinflammatory cytokines. Interestingly, most neuropeptide receptors are seven-transmembrane domaincontaining receptors, which exert their function by activating heterotrimeric G proteins. Neuropeptides are mainly expressed and active in the central and peripheral nervous systems. However, these peptides can also be unexpectedly produced and are functional in other peripheral tissues. For example, adrenocorticotropic hormone/corticotropin (ACTH) is not only produced by pituitary cells but also to a limited extent by leukocytes.2 Endogenous opioids are expressed by leukocytes and play an important role in peripheral analgesic effects.29 In addition to being produced in the pituitary gland, α-melanocytestimulating hormones (αMSH) are also highly expressed in the skin and the gastro intestinal (GI) tract cells.21 Substance P mRNA and protein have been detected in the thymic medulla and purified CD5+ thymocytes.27 The neuropeptides of the HPA axis play a profound role in inflammation. Stressful stimuli activate the HPA axis through the release of a sequential series of neuropeptide hormones, beginning with the production of hypothalamic corticotropin-releasing hormone (CRH) and followed by pituitary derived ACTH, culminating in the secretion of glucocorticoids, potent anti-inflammatory hormones produced by the adrenal cortex.6 Vasopressin (AVP) potentiates 681
682
TABLE 1 Neuropeptides Regulating Receptor Expressing Leukocytes Size
Receptors in immune system
Immune effects
Nonimmune effects
CRH
41aa
Neutrophils, eosinophils, thymus, spleen
Enhances the production of immunosuppresive glucocorticoids through the HPA axis, enhances peripheral inflammation. Urocortin (Ucn), UcnI, and UcnII share similar properties.
Endocrine-signaling peptide involved in the stress response
Urocortin (Ucn)
40aa
Monocytes, macrophages, dendritic cells, polymorphonuclear cells, T cells
Inhibits inflammatory cytokines and chemokines production, T cell proliferation, and TH1 response; enhances IL-10/transforming growth factor (TGF)-β1 production; induces regulatory T cells.
Regulates vasodilatation, bronchodilatation, cardiac output, smooth muscle relaxation, food intake, and ACTH secretion.
Somatostatin
14aa, or 28aa
T cells, monocytes
Inhibits the secretion of proinflammatory cytokines and antibodies by immune cells; inhibits lymphocyte proliferation.
Inhibits secretion of numerous growth hormones.
Cortistatin
17aa
Monocytes, macrophages, dendritic cells, T cells
Inhibits inflammatory cytokines and chemokines production, T cell proliferation, and TH1 response; induces regulatory T cells.
Inhibits locomotor activity, regulates growth hormone.
Vasopressin (AVP)
9aa
T cells, B cells, monocytes
Enhances production of immunosuppresive glucocorticoids through the HPA axis, enhances secretion of IFN-γ by T-cells.
Potentiates CRH effects, responds to osmotic and hemodynamic stress.
Gastrin-releasing peptides (GRP)
27aa
Macrophage, T cells, natural killer cells
Stimulates phagocytic activities of macrophages, inhibits Con-A induced proliferation of lymphocytes. Bombesin and neuromedin C share similar properties.
Activates the sympathetic nervous system to modulate stress, fear, and anxiety responses.
Met-enkephalin and endorphins
5aa
T cell, B cells monocytes, neutrophils, natural killer cells
Induces heterologous desensitization of chemokine receptors, inhibits natural killer cell activity, suppresses IL2 and IFNγ production.
Analgesic peptides, induces the secretion of corticosterone.
ACTH
39aa
T helper cells, B cells, macrophages
Enhances production of immunosuppresive glucocorticoids through the HPA axis.
Endocrine-signaling peptides involved in the response to stress.
αMSH (melanocortin)
13aa
Monocytes, macrophages, natural killer cells, T helper cells, B cells, and dendritic cells
Downregulates the production of proinflammatory cytokines, downregulates the expression of costimulatory molecules (CD86, CD40, ICAM-1) on antigen-presenting dendritic cells, upregulates IL-10. inhibits cutaneous inflammation, inhibits T cell proliferation, and induces regulatory T cells.
Regulation of energy homeostasis.
Chapter | 92 Neuroimmune Peptides
Neuropeptides
36aa
Monocytes, T cells, B cells, natural killer cells
Elicits neurogenic inflammation by inducing the secretion of substance P, contributes to colitis, potentiates paw edema; enhances T cell adhesion to fibronectin; increases release of oxidative reagents by neutrophils, suppresses NK cell activity; enhances phagocytosis by monocyte.
Regulates energy balance, food intake, and antihyperalgesia, antimicrobial peptide, affects skin color, antipyretic effects.
VIP/PACAP
28aa
T cells, mast cells, macrophages, monocytes, dentritic cells, polymorphonuclear cells
Inhibits leukocyte recruitment, cytokine production; polarizes TH2 responses, induces T lymphocyte adhesion and chemotaxis, inhibits TH1 response and recruitment, enhances tolerogenic DC generation. PACAP possesses similar anti-inflammatory activities.
Neurotransmitter, secretagogue, neuroprotective, neurotrophic, and vasodilator.
Substance P (neurokinin1, tachykinin 1)
11aa
T cells, macrophages, dendritic cells
Contributes to neurogenic inflammation, involves in various respiratory diseases and pancreatitis. Substance K (neurokinin A) possesses similar proinflammatory activities.
Induces hyperalgesia
CGRP
37aa
T cells, B cells, dendritic cells
Contributes to neurogenic inflammation, involves in various aspiratory diseases.
Induces vasodilatation
Bradykinin
9aa
Monocytes, neutrophils, eosinophils, T cells
Induces chemotaxis of neutrophils, Induces hyperalgesia; vasodilator. stimulates the secretion of superoxide radicals, exacerbates infection, contributes to ischemia reperfusion, involved in respiratory diseases.
Adrenomedullin (AM)
52aa
Monocytes, macrophages
Inhibits inflammatory cytokines and chemokine production, T cell proliferation, and TH1 response; induces regulatory T cells; Stimulates IL-10/TGF-β production.
Regulates vasodilatation, bronchodilatation, cardiac output, and smooth muscle relaxation.
Ghrelin
28aa
Monocytes, macrophages, dendritic cells, T cells
Inhibits inflammatory cytokines and chemokine production; suppresses T cell proliferation, and TH1 response (IL-2 and IFN-γ production); induces regulatory T cells
Regulates cardiac output, appetite, adiposity, vasodilatation; enhances GI secretion, and gastric motility.
SECTION | IX Handbook of Biologically Active Peptides: Immune/Inflammatory Peptides
Neuropeptide Y
CRH: corticotropin-releasing hormone; αMSH: alpha-melanocyte-stimulating hormone; ACTH: adrenocorticotropic hormone/corticotropin; CGRP: calcitonin-gene-related peptide; VIP: vasoactive intestinal polypeptide.
683
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the capacity of CRH to activate the HPA axis. The resultant elevated glucocorticoid concentrations in the circulation contribute to stress-induced immunosuppression. Surprisingly, CRH and AVP are also produced by leukocytes, and their receptors are expressed by leukocytes. Although hypothalamic CRH and AVP have indirect anti-inflammatory effects through the stimulation of glucocorticoids, these peptides seem to have direct proinflammatory effects in the peripheral tissues. AVP stimulates the secretion of interferon-γ by T-lymphocytes.18 CRH elicits the production of interleukin (IL)-1 by human monocytes and enhances mouse natural killer (NK) cell activity.5 CRH and its family members, urocortin (Ucn), UcnI, and UcnII have been shown to exacerbate symptoms of experimental autoimmune encephalomyelitis and toxin A-induced inflammatory diarrhea.1 The expression of Ucn is upregulated during inflammation.17 Ucn induces apoptosis of macrophage during inflammation, suggesting its important anti-inflammatory effect.31 Regarding innate immunity, Ucn inhibits the production of several proinflammatory cytokines, such as tumor necrosis factor (TNF)α, IL-6, and IL-12, and further in vivo disease-associated (i.e. sepsis and inflammatory bowel disease) studies support the anti-inflammatory role of Ucn.14 Thus, their antagonists have been tested as therapeutics for arthritis and preliminary results are encouraging.33 Inflammation induces hyperalgesia. This is in part attributable to the chemokine receptor-induced desensitization of analgesic opioid receptors and concomitant sensitization of algesic vanilloid receptors transient receptor potential vanilloid (TRPV)1 on neurons.34,35 Conversely, opioid receptors on leukocytes have immunosuppressive effects. Met-enkephalin, an endogenous opioid, is an analgesic peptide of 5 amino acids.3 It exerts immunosuppressive effects by heterologous desensitization of chemokine receptors and enhancing the secretion of corticosteroids.23 TRPV1 is also expressed by leukocytes, but its immune function remains unknown. Painful stimuli activate peripheral neurons to release several immunostimulatory peptides, including substance P and calcitonin-gene-related peptide (CGRP). These peptides have proinflammatory effects and are associated with neurogenic inflammation. Substance P, a hyperalgesic peptide, belongs to the tachykinin family. It stimulates the influx of neutrophils and eosinophils into the human dermis, induces the secretion of TNFα by macrophages, and it enhances leukocyte adhesion to endothelial cells, which may contribute to its proinflammatory effects in various respiratory diseases, pancreatitis, and inflammatory bowel disease.24 Substance K, another peptide in the tachykinin family, possesses similar proinflammatory effects. CGRP is also involved in neurogenic respiratory diseases such as asthma, chronic obstructive pulmonary disease, or chronic cough.28 Adrenomedullin (AM) could function as an endogenous
Chapter | 92 Neuroimmune Peptides
anti-inflammatory immune modulator with a high structural homology to CGRP.11 Unlike CGRP, AM could effectively prevent arthritis and sepsis through inhibiting the inflammatory response in these autoimmune/inflammatory diseases.12,14 Neuropeptide Y (NPY), a key peptide regulating energy balance and food intake in central nervous system (CNS), also induces the secretion of substance P by peripheral neurons, contributing to colitis and paw edema in animal models of inflammation.10 Further, NPY directly enhances T cell adhesion to fibronectin20 and plays a major role in the regulation of Th1 responses.26 Bradykinin, another hyperalgesic peptide, facilitates septic shock, exacerbates ischemia reperfusion, and enhances airway inflammation based on its vasodilatory effects.4 There several other neuropeptides that downregulate immune responses. Vasoactive intestinal polypeptide (VIP) has immunosuppressive effects based on its capacity to inhibit leukocyte recruitment to inflammatory sites. VIP also induces polarization to the T helper (TH)2 type of antibody-based allergic responses.25 In addition, VIP induces the differentiation of tolerogenic dentritic cells that promote generation of antigen specific Treg cells.15 αMSH downregulates the production of proinflammatory cytokines, inhibits the expression of costimulatory molecules (CD86, CD40, and intercellular adhesion molecule (ICAM)-1) on dendritic cells, and upregulates IL-10, resulting in immunosuppression.22 An increasing body of evidence shows that VIP and αMSH could regulate TH1/TH2/Treg immune homeostasis and induce immune tolerance and inhibit autoimmune response through inhibiting the production of inflammatory cytokines and chemokines, polarizing the differentiation of T cells toward TH2 or Treg, and suppressing the activation of autoreactive T cells by IL-10 and TGFβ.11,13 Moreover, both VIP and αMSH inhibit phagocytic activity as well as the migration and adherence of macrophages and neutrophils.9 Ghrelin is one of the anti-inflammatory neuropeptides with an immunomodulatory role through binding to its receptor growth hormone secretagog receptor (GHSR), and subsequently activating the cyclic adenosine monophosphate-protein kinase A signaling pathway that is associated with anti-inflammatory actions.13 Somatostatin inhibits the secretion of interferons (IFN)-γ and cerebrospinal fluid, enhances the secretion of IL-10 and IL-4, downregulates the secretion of antibodies by B lymphocytes, and impairs lymphocyte proliferation.30 Cortistatin has a strong structural similarity to somatostatin. Cortistatin is expressed in various immune cells, including monocytes, macrophages, lymphocytes, and dentritic cells, with its expression upregulated on cell differentiation and activation, suggesting that cortistatin may act as a major immune regulator.11 In addition, both in vitro and in vivo studies show that cortistatin functions more efficiently than somatostatin in its antiinflammatory responses, probably because of the capacity
SECTION | IX Handbook of Biologically Active Peptides: Immune/Inflammatory Peptides
of cortistatin to activate different receptors and signaling pathways.7,16 Cortistatin cannot only bind to somatostatin receptor subtypes (SSTs), but also to GHSR, thus leading to the activation of both cAMP-independent (SST mediated) and -dependent (GHSR-mediated) signaling.13,32 Gastrinreleasing peptide (GRP) and neuromedin C belong to the bombesin peptide family. They stimulate phagocytic activities of macrophages but inhibit concanavalin-A induced proliferation of lymphocytes.8 In summary, increasing evidence has confirmed the production of neuropeptides and the expression of their receptors by cells of the immune system. Further, neuropeptides directly contribute to a wide range of diseases, such as stress-induced immunosuppresion, asthma, and inflammatory bowel disease. However, many more studies are needed to connect in vitro observations, based on the use of isolated leukocytes, to the in vivo systemic effects of neuropeptides in disease. Further, it is critical to understand that the anatomical and temporal distribution of these peptides may determine their overall effects on immune responses. For example, CRH acts as an anti-inflammatory agent when it exerts its effects in the CNS to stimulate the production of ACTH and then glucocorticoids. However, in the peripheral tissues, CRH is proinflammatory, and its antagonists can be used to treat arthritis in animal models. Experiments from various animal models with knockout of VIP, AM, VIP/ PACAP receptors, or Ucn result in endotoxemia and lung inflammation as well as Th1-mediated responses in vivo, and further highlight the physiological relevance of these neuroimmune peptides in certain inflammatory and autoimmune conditions. In summary, a broad range of neuropeptides is capable of influencing immune responses. They may serve to integrate a host’s immune and nervous system response to injurious environmental stimuli. The physiological relevance of immunoregulatory activity of these neuropeptides needs further investigation.
ACKNOWLEDGMENTS The authors thank Dr. Esther M. Sternberg for reviewing the manuscript and constructive discussion. This research was supported [in part or whole] by the Intramural Research Program of the National Institute Health (NIH), National Cancer Institute.
REFERENCES 1. Anton PM, Gay J, Mykoniatis A, Pan A, O’Brien M, Brown D, et al. Corticotropin-releasing hormone (CRH) requirement in Clostridium difficile toxin A-mediated intestinal inflammation. Proc Natl Acad Sci U S A 2004;101:8503–8. 2. Blalock JE. Production of peptide hormones and neurotransmitters by the immune system. Chem Immunol 1992;52:1–24. 3. Bodnar RJ, Klein GE. Endogenous opiates and behavior. Peptides 2003;2004(25):2205–56.
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4. Calixto JB, Medeiros R, Fernandes ES, Ferreira J, Cabrini DA, Campos MM. Kinin B1 receptors: key G-protein-coupled receptors and their role in inflammatory and painful processes. Br J Pharmacol 2004;143:803–18. 5. Carr DJ, DeCosta BR, Jacobson AE, Rice KC, Blalock JE. Corticotropin-releasing hormone augments natural killer cell activity through a naloxone-sensitive pathway. J Neuroimmunol 1990;28: 53–61. 6. Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol 2005;67:259–84. 7. Deghenghi R, Papotti M, Ghigo E, Muccioli G. Cortistatin, but not somatostatin, binds to growth hormone secretagogue (GHS) receptors of human pituitary gland. J Endocrinol Invest 2001;24: RC1–3. 8. Del Rio M, Hernanz A, de la Fuente M. Bombesin, gastrin-releasing peptide, and neuromedin C modulate murine lymphocyte proliferation through adherent accessory cells and activate protein kinase C. Peptides 1994;15:15–22. 9. Delgado M, Pozo D, Ganea D. The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev 2004;56: 249–90. 10. Dimitrijevic M, Stanojevic S, Vujic V, Kovacevic-Jovanovic V, Beck-Sickinger A, Demuth H, et al. Effect of neuropeptide Y on inflammatory paw edema in the rat: involvement of peripheral NPY Y1 and Y5 receptors and interaction with dipeptidyl-peptidase IV (CD26). J Neuroimmunol 2002;129:35–42. 11. Gonzalez-Rey E, Chorny A, Delgado M. Regulation of immune tolerance by anti-inflammatory neuropeptides. Nat Reviews Immunol 2007;7:52–63. 12. Gonzalez-Rey E, Chorny A, O’Valle F, Delgado M. Adrenomedullin protects from experimental arthritis by down-regulating inflammation and Th1 response and inducing regulatory T cells. Am J Pathol 2007;170:263–71. 13. Gonzalez-Rey E, Delgado M. Anti-inflammatory neuropeptide receptors: new therapeutic targets for immune disorders? Trends Pharmacol Sci 2007;28:482–91. 14. Gonzalez-Rey E, Fernandez-Martin A, Chorny A, Delgado M. Therapeutic effect of urocortin and adrenomedullin in a murine model of Crohn’s disease. Gut 2006;55:824–32. 15. Gonzalez-Rey E, Ganea D, Delgado M. Neuropeptides: keeping the balance between pathogen immunity and immune tolerance. Curr Opin Pharmacol 2010;10:473–81. 16. Gonzalez-Rey E, Varela N, Sheibanie AF, Chorny A, Ganea D, Delgado M. Cortistatin, an antiinflammatory peptide with therapeutic action in inflammatory bowel disease. Proc Natl Acad Sci U S A 2006;103:4228–33. 17. Gravanis A, Margioris AN. The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications. Curr Med Chem 2005;12:1503–12. 18. Johnson HM, Torres BA. A novel arginine vasopressin-binding peptide that blocks arginine vasopressin modulation of immune function. J Immunol 1988;141:2420–3. 19. Law PY, Wong YH, Loh HH. Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol 2000;40: 389–430. 20. Levite M, Cahalon L, Hershkoviz R, Steinman L, Lider O. Neuropeptides, via specific receptors, regulate T cell adhesion to fibronectin. J Immunol 1998;160:993–1000.
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21. Loir B, Bouchard B, Morandini R, Del Marmol V, Deraemaecker R, Garcia-Borron JC, et al. Immunoreactive alpha-melanotropin as an autocrine effector in human melanoma cells. Eur J Biochem 1997; 244:923–30. 22. Luger TA, Scholzen TE, Brzoska T, Bohm M. New insights into the functions of alpha-MSH and related peptides in the immune system. Ann N Y Acad Sci 2003;994:133–40. 23. McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ. Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 2001;62:111–23. 24. O’Connor TM, O’Connell J, O’Brien DI, Goode T, Bredin CP, Shanahan F. The role of substance P in inflammatory disease. J Cell Physiol 2004;201:167–80. 25. Pozo D, Delgado M. The many faces of VIP in neuroimmunology: a cytokine rather a neuropeptide? FASEB J 2004;18:1325–34. 26. Prod’homme T, Weber MS, Steinman L, Zamvil SS. A neuropeptide in immune-mediated inflammation, Y? Trends Immunol 2006;27:164–7. 27. Santoni G, Amantini C, Lucciarini R, Pompei P, Perfumi M, Nabissi M, et al. Expression of substance P and its neurokinin-1 receptor on thymocytes: functional relevance in the regulation of thymocyte apoptosis and proliferation. Neuroimmunomodulation 2002;10:232–46. 28. Springer J, Geppetti P, Fischer A, Groneberg DA. Calcitonin generelated peptide as inflammatory mediator. Pulm Pharmacol Ther 2003;16:121–30.
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29. Stein C, Schafer M, Machelska H. Attacking pain at its source: new perspectives on opioids. Nat Med 2003;9:1003–8. 30. ten Bokum AM, Hofland LJ, van Hagen PM. Somatostatin and somatostatin receptors in the immune system: a review. Eur Cytokine Netw 2000;11:161–76. 31. Tsatsanis C, Androulidaki A, Dermitzaki E, Charalampopoulos I, Spiess J, Gravanis A, et al. Urocortin 1 and urocortin 2 induce macrophage apoptosis via CRFR2. FEBS Lett 2005;579:4259–64. 32. Varela N, Chorny A, Gonzalez-Rey E, Delgado M. Tuning inflammation with anti-inflammatory neuropeptides. Expert Opin Biol Ther 2007;7:461–78. 33. Webster EL, Barrientos RM, Contoreggi C, Isaac MG, Ligier S, Gabry KE, et al. Corticotropin releasing hormone (CRH) antagonist attenuates adjuvant induced arthritis: role of CRH in peripheral inflammation. J Rheumatol 2002;29:1252–61. 34. Zhang N, Inan S, Cowan A, Sun R, Wang JM, Rogers TJ, et al. A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1. Proc Natl Acad Sci U S A 2005;102: 4536–41. 35. Zhang N, Rogers TJ, Caterina M, Oppenheim JJ. Proinflammatory chemokines, such as C-C chemokine ligand 3, desensitize muopioid receptors on dorsal root ganglia neurons. J Immunol 2004;173: 594–9.