Skip to main content
SpringerLink
Log in

The Cholinergic Anti-inflammatory Pathway: A Missing Link in Neuroimmunomodulation

  • In Overview
  • Published:
Molecular Medicine Aims and scope Submit manuscript

Abstract

This review outlines the mechanisms underlying the interaction between the nervous and immune systems of the host in response to an immune challenge. The main focus is the cholinergic anti-inflammatory pathway, which we recently described as a novel function of the efferent vagus nerve. This pathway plays a critical role in controlling the inflammatory response through interaction with peripheral α7 subunit-containing nicotinic acetylcholine receptors expressed on macrophages. We describe the modulation of systemic and local inflammation by the cholinergic anti-inflammatory pathway and its function as an interface between the brain and the immune system. The clinical implications of this novel mechanism also are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Sell S. (2001) Immunology, immunopathology, and immunity (6th ed). ASM Press, Washington, D.C.

    Book  Google Scholar 

  2. Baumann H, Gauldie J. (1994) The acute phase response. Immunol. Today 15:74–80.

    Article  CAS  PubMed  Google Scholar 

  3. Koj A. (1997) Initiation of acute phase response and synthesis of cytokines. Biochim. Biophys. Acta. 1317:84–94.

    Article  Google Scholar 

  4. Tracey KJ et al. (1986) Shock and tissues injury induced by recombinant human cachectin. Science 234:470–4.

    Article  CAS  PubMed  Google Scholar 

  5. Wang H et al. (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–51.

    Article  CAS  PubMed  Google Scholar 

  6. Wang H, Yang H, Czura CJ, Sama AE, Tracey KJ. (2001) HMGB1 as a late mediator of lethal systemic inflammation. Am. J. Respir. Crit. Care Med. 164:1768–73.

    Article  CAS  PubMed  Google Scholar 

  7. Sporn MB. (1997) The importance of context in cytokine action. Kidney Int. 51:1352–4.

    Article  CAS  PubMed  Google Scholar 

  8. Kushner I. (1998) Semantics, inflammation, cytokines and common sense. Cytokine Growth Factor Rev. 9:191–6.

    Article  CAS  PubMed  Google Scholar 

  9. Reichlin S. (1993) Neuroendocrine-immune interactions. New Engl. J. Med. 329:1246–53.

    Article  CAS  PubMed  Google Scholar 

  10. Peristein RS, Whitnall MH, Abrams JS, Mougey EH, Neta R. (1993) Synergistic roles of interleukin-6, interleukin-1 and tumor necrosis factor in adrenocorticotropin response to bacterial lipopolysaccharide in vivo. Endocrinology 132:946–52.

    Article  Google Scholar 

  11. Gaillard RC. (1995) Neuroendocrine-immune system interactions. Trends Endocrinol. Metab. 7:303–9.

    Google Scholar 

  12. Mulla A, Buchingham JC. (1999) Regulation of the hypothalamo-pituitary-adrenal axis by cytokines. Baillieres Best. Prac. Res. Clin. Endocriol. Metab. 13:503–21.

    Article  CAS  Google Scholar 

  13. Rivest S. (2001) How circulating cytokines trigger the neural circuits that control the hypothalamic-pituitary-adrenal axis. Psychoneuroendocrinology 26:761–88.

    Article  CAS  PubMed  Google Scholar 

  14. Webster JI, Tonelli L, Sternberg EM. (2002) Neuroendocrine regulation of immunity. Annu. Rev. Immunol. 20:125–63.

    Article  CAS  PubMed  Google Scholar 

  15. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. (2000) The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol. Rev. 52:595–638.

    CAS  PubMed  Google Scholar 

  16. Borovikova LV et al. (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–61.

    Article  CAS  PubMed  Google Scholar 

  17. Tracey KJ, Czura CJ, Ivanova S. (2001) Mind over immunity. FASEB J. 15:1575–6.

    Article  CAS  PubMed  Google Scholar 

  18. Tracey KJ. (2002) The inflammatory reflex. Nature 420:853–9.

    Article  CAS  PubMed  Google Scholar 

  19. Blalock JE. (2002) Harnessing a neural-immune circuit to control inflammation and shock. J. Exp. Med. 195:F25–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Watkins LR, Maier SF, Goehler LE. (1995) Cytokine-to-brain communication: a review and analysis of alternative mechanisms. Life Sci. 57:1011–26.

    Article  CAS  PubMed  Google Scholar 

  21. Elmquist JK, Scammell TE, Saper CB. (1997) Mechanisms of CNS response to systemic immune challenge: the febrile response. Trends Neurosci. 20:565–9.

    Article  CAS  PubMed  Google Scholar 

  22. Goehler LE, Gaykema RPA, Hansen MK, Anderson K, Maier SF, Watkins L. (2000) Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton. Neurosci. 85:49–59.

    Article  CAS  PubMed  Google Scholar 

  23. Goehler LE et al. (1999) Interleukin-1 in immune cells of the abdominal vagus nerve: a link between the immune and nervous system? J. Neurosci. 19:2799–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Berthhoud HR, Neuhuber WL. (2000) Functional anatomy of afferent vagal system. Auton. Neurosci. 85:1–17.

    Article  Google Scholar 

  25. Iversen S, Iversen L, Saper CB. (2000) The autonomic nervous system and the hypothalamus. In: Principles in Neural Science. 4th ed. Kendel ER, Schwartz JH, Jessel TM (eds.) McGraw Hill, New York. pp. 960–81.

    Google Scholar 

  26. Gaykema RPA, Dijkstra I, Tilders FJH. (1995) Subdiaphragmic vagotomy suppresses endotoxin-induced activation of hypothalamic corticotropin-releasing hormones neurons and ACTH secretion. Endocrinology 136:4717–20.

    Article  CAS  PubMed  Google Scholar 

  27. Ishizuka Y et al. (1997) Effects of area postrema lesion and abdominal vagotomy on interleukin-1β-induced norepinephrine release in the hypothalamic paraventricular nucleus region in the rat. Neurosci. Lett. 223:57–60.

    Article  CAS  PubMed  Google Scholar 

  28. Hermann GE, Emch GS, Tovar CA, Rogers RC. (2001) C-Fos generation in the dorsal vagal complex after systemic endotoxin is not dependent on the vagus nerve. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 280:R289–99.

    Article  CAS  Google Scholar 

  29. Van Dam AM et al. (2000) Vagotomy does not inhibit high dose LPS-indiced interleukin-1β immunoreactivity in the rat brain and pituitary gland. Neurosci. Lett. 285:169–72.

    Article  PubMed  Google Scholar 

  30. Hansen MK et al. (2000) Effects of vagotomy on serum endotoxin, cytokines and corticosterone after intraperitoneal lipopolysaccharide. Am. J. Physiol. 278:R331–6.

    Article  CAS  Google Scholar 

  31. Hopkins SJ, Rothwell N. (1995) Cytokines and nervous system I: expression and recognition. Trends Neurosci. 18:83–8.

    Article  CAS  PubMed  Google Scholar 

  32. Szelényi J. (2001) Cytokines and the central nervous system. Brain Res. Bull. 54:329–459.

    Article  PubMed  Google Scholar 

  33. Rivest S et al. (2000) How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli. Proc. Soc. Exp. Biol. Med. 223:22–38.

    Article  CAS  PubMed  Google Scholar 

  34. Banks WA, Kastin AJ, Broadwell RD. (1995) Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation 2:241–8.

    Article  CAS  PubMed  Google Scholar 

  35. Nadeau S, Rivest S. (1999) Effects of circulating tumor necrosing factor on the neuronal activity and expression on the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood-brain barrier. Neuroscience 93:1449–64.

    Article  CAS  PubMed  Google Scholar 

  36. Ek M, Engblom D, Saha S, Blomqvist A, Jacobsson P-J, Ericsson-Dahlstrand A. (2001) Inflammatory response: pathway across the blood-brain barrier. Nature 410:430–1.

    Article  CAS  PubMed  Google Scholar 

  37. Buller KM. (2001) Circumventricular organs: gateways to the brain. Role of circumventricular organs in pro-inflammatory cytokine-induced activation of the hypothalamic-pituitary-adrenal axis. Clin. Experiment. Pharmacol. Physiol. 28:581–9.

    Article  CAS  Google Scholar 

  38. Afifi AK, Bergmann RA. (1998) Medulla oblongata. In: Functional neuroanatomy. McGraw-Hill, New York, p. 117.

    Google Scholar 

  39. Rogers RC, McCann MJ. (1993) Intramedullary connections of the gastric region in the solitary nucleus: a biocytin histochemical tracing study in the rat. J. Auton Nerv. Syst. 42:119–30.

    Article  CAS  PubMed  Google Scholar 

  40. Rogers RC, Hermann GE, Travagli RA. (1999) Brainstem pathways responsible for the oesophageal control of gastric motility and tone in the rat. J. Physiol. 514:369–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rothwell NJ, Hopkins SL. (1995) Cytokines and the nervous system II: actions and mechanism of action. Trends Neurosci. 18:130–6.

    Article  CAS  PubMed  Google Scholar 

  42. Benveniste EN. (1998) Cytokine actions in the central nervous system. Cytokine Growth Factor Rev. 9:259–75.

    Article  CAS  PubMed  Google Scholar 

  43. Hallenbeck JM. (2002) The many faces of tumor necrosis factor in stroke. Nature Med. 8:1363–8.

    Article  CAS  PubMed  Google Scholar 

  44. Lilly MP, Gann DS. (1992) The hypothalamic-pituitary-adrenal-immune axis: a critical assessment. Arch. Surg. 127:1463–74.

    Article  CAS  PubMed  Google Scholar 

  45. McEwen BS et al. (1997) The role of adrenocorticoides as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res. Rev. 23:79–133.

    Article  CAS  PubMed  Google Scholar 

  46. Karalis K, Muglia LJ, Bae D, Hildebrand H, Majzoub JA. (1997) CRH and the immune system. J. Immunology 72:131–6.

    CAS  Google Scholar 

  47. Adcock IM. (2000) Molecular mechanisms of glucocorticoid action. Pulmon. Pharmacol. Ther. 13:115–26.

    Article  CAS  Google Scholar 

  48. Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS. (1995) Role of transcriptional activation of I κB alpha in mediation of immunosuppression by glucocorticoids. Science 270:283–6.

    Article  CAS  PubMed  Google Scholar 

  49. McKay LI, Cidlowski JA. (1999) Molecular control of immune/inflammatory responses: interactions between nuclear factor κB and steroid receptor-signaling pathways. Endocrine Rev. 20:435–59.

    CAS  Google Scholar 

  50. Ghosh S, May MJ, Kopp EB. (1998) NF-κB and Rel proteins: evolutionary conserved mediators of immune responses. Annu. Rev. Immunol. 16:225–60.

    Article  CAS  PubMed  Google Scholar 

  51. Hasko G, Szabo C. (1998) Regulation of cytokine and chemokine production by transmitters and co-transmitters of the autonomic nervous system. Biochem. Pharmacol. 56:1079–87.

    Article  CAS  PubMed  Google Scholar 

  52. Bellinger DL, Lorton CL, Felton DL. (2001) Innervation of lymphoid organs: association of nerves with cells of the immune system and their implications in disease. In: Psychoneuroimmunology. Ader R, Felten DI, Cohen N (eds.). 3rd ed. Academic Press, New York, pp. 55.

    Google Scholar 

  53. van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF. (1996) Epinephrine inhibits tumor necrosis factor-α and potentiates interleukin-10 production during human endotoxemia. J. Clin. Invest. 97:713–9.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Madden KS, Sanders VM, Felten DL. (1995) Catecholamine influences and sympathetic neuronal modulation of immune responsiveness. Annu. Rev. Pharmacol. Toxicol. 35:417–48.

    Article  CAS  PubMed  Google Scholar 

  55. Zhou M, Yang S, Koo DJ, Ornan DA, Chaudry IH, Wang P. (2001) The role of Kupffer cell α2-adrenoceptors in norepinephrine-induced TNF-α production. Biochim. Biophys. Acta. 1537:49–57.

    Article  CAS  PubMed  Google Scholar 

  56. Lipton JM, Catania A. (1997) Anti-inflammatory actions of the neuroimmunomodulator α-MSH. Immunol. Today 140:140–5.

    Article  Google Scholar 

  57. Catania A, Airaghi L, Colombo G, Lipton JM. (2000) α-Melanocyte-stimulating hormone in normal human physiology and disease states. Trends Exp. Med. 11:304–8.

    CAS  Google Scholar 

  58. Macaluso A et al. (1994) Anti-inflammatory influences of α-MSH molecules: central neurogenic and peripheral action. J. Neurosci. 14:2377–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Catania A, Suffredini AF, Lipton JM. (1995) Endotoxin causes release of α-melanocyte-stimulating hormone in normal human subjects. Neuroimmunomodulation 2:258–62.

    Article  CAS  PubMed  Google Scholar 

  60. Janson L, Holmdahl R. (1998) Estrogen-mediated immunosupression in autoimmune diseases. Inflamm. Res. 47:290–301.

    Article  Google Scholar 

  61. Behl C. (2002) Oestrogen as a neuroprotective hormone. Nature Rev. Neurosci. 3:433–42.

    Article  CAS  Google Scholar 

  62. DaSilva JA, Colville-Nash P, Spector TD, Scott DL, Willoughby DA. (1993) Inflammation-induced cartilage degradation in female rodents. Protective role of sex hormones. Arthritis Rhem. 36:1007–15.

    Article  CAS  Google Scholar 

  63. Deshpande R, Khalili H, Pergolizzi RG, Michael SD, Chang MD. (1997) Estradiol down-regulates LPS-induced cytokine production and NF-κB activation in murine macrophages. Am. J. Reprod. Immunol. 38:46–54.

    Article  CAS  PubMed  Google Scholar 

  64. Srivastava S, Weitzmann MN, Cenci S, Ross FP, Adler S, Pacifici R. (1999) Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and Jun D. J. Clin. Invest. 104:503–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Strom TB, Deisseroth A, Morganroth J, Carpenter CB, Merrill JP. (1972) Alteration of the cytotoxic action of sensitized lymphocytes by cholinergic agents and activators of adenylate cyclase. Proc. Natl. Acad. Sci. U.S.A. 69:2995–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Antonica A, Magni F, Mearini L, Paolocci N. (1994) Vagal control of lymphocyte release from rat thymus. J. Auton. Nerv. Syst. 48:187–97.

    Article  CAS  PubMed  Google Scholar 

  67. Niijima A, Hori T, Katafuchi T, Ichijo T. (1995) The effect of interleukin-β on the efferent activity of the vagus nerve to the thymus. J. Auton. Nerv. Syst. 54: 137–44.

    Article  CAS  PubMed  Google Scholar 

  68. Hori T, Katafuchi T, Take S, Shimizu N, Niijima A. (1995) The autonomic nervous system as a communication channel between the brain and the immune system. Neuroimmunomodulation 2:203–15.

    Article  CAS  PubMed  Google Scholar 

  69. Borovikova LV et al. (2000) Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton. Neurosci. 85:141–7.

    Article  CAS  PubMed  Google Scholar 

  70. Caulfield P, Birdsall NJM. (1998) Intl. union of pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol. Reviews 50:279–90.

    CAS  Google Scholar 

  71. Lindstrom J. (1997) Nicotinic acetylcholine receptors in health and disease. Mol. Neurobiol. 15:193–222.

    Article  CAS  PubMed  Google Scholar 

  72. Hiemke C et al. (1996) Expression of alpha subunit genes of nicotinic acetylcholine receptors in human lymphocytes. Neurosci. Lett. 214:171–4.

    Article  CAS  PubMed  Google Scholar 

  73. Mita Y, Dobashi K, Suzuki K, Mori M, Nakazawa T. (1996) Induction of muscarinic receptor subtypes in monocytic/macrophagic cells differentiated from EoL-1 cells. Eur. J. Pharmacol. 297:121–7.

    Article  CAS  PubMed  Google Scholar 

  74. Toyabe S et al. (1997) Identification o as thymus in mice. Immunol. 92:201–5.

    Article  CAS  Google Scholar 

  75. Sato KZ et al. (1999) Diversity of mRNA expression for muscarine acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines. Neurosci. Lett. 266: 17–20.

    Article  CAS  PubMed  Google Scholar 

  76. Walch L, Brink C, Norel X. (2001) The muscarinic receptor subtypes in human blood vessels. Therapie 56:223–6.

    CAS  PubMed  Google Scholar 

  77. Tayebati SK, El-Assouad D, Ricci A, Amenta F. (2002) Immunochemical and immunocytochemical characterization of cholinergic markers in human peripheral blood lymphocytes. J. Neuroimmunol. 132:147–55.

    Article  CAS  PubMed  Google Scholar 

  78. Kawashima K, Fujii T. (2000) Extraneural cholinergic system in lymphocytes. Pharmacol. Ther. 86:29–48.

    Article  CAS  PubMed  Google Scholar 

  79. Tracey KJ et al. (1987) Anti-cachectin/TNF-monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330:662–4.

    Article  CAS  PubMed  Google Scholar 

  80. Bernik TR et al. (2002) Pharmacological stimulation of the cholinergic antiinflammatory pathway. J. Exp. Med. 195:1–9.

    Article  Google Scholar 

  81. Villa P et al. (1997) Inhibition of multiple pro-inflammatory mediators (TNF, IL-6, and NO) abrogate lethality in a murine mode of polymicrobial sepsis. J. Endot. Res. 4:197–204.

    Article  CAS  Google Scholar 

  82. Martiney JA et al. (1998) Prevention and treatment of experimental autoimmune encephalomyelitis by CNI-1493, a macrophage deactivating agent. J. Immunol. 160:5588–95.

    CAS  PubMed  Google Scholar 

  83. Akerlund K et al. (1999) Anti-inflammatory effect of a new TNFα inhibitor (CNI-1493) in collagen-induced arthritis in rats. J. Clin. Exp. Immunol. 115:32–41.

    Article  CAS  Google Scholar 

  84. Bianchi M et al. (1996) Suppression of pro-inflammatory cytokines in monocytes by tetravalent guanylhidrazone. J. Exp. Med. 83:927–36.

    Article  Google Scholar 

  85. Wang H, Zhang M, Bianchi M, Sherry B, Sama A, Tracey KJ. (1998) Fetuin (α-2-HS-Glycoprotein) opsonizes cationic macrophage-deactivating molecules. Proc. Natl. Acad. Sci. U.S.A. 95:14429–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tracey KJ. (1998) Suppression of TNF and other pro-inflammatory cytokines by tetravalent guanylhydrazone CNI-1492. Prog. Clin. Biol. Res. 397:335–43.

    CAS  PubMed  Google Scholar 

  87. Meistrell MEIII et al. (1997) TNF is a brain-damaging cytokine in cerebral ischemia. Shock 8:341–8.

    Article  PubMed  Google Scholar 

  88. Hoover DB, Hancock JC, DePorter TE. (1985) Effect of vagotomy on cholinergic parameters in nuclei of rat medulla oblongata. Brain Res. Bull. 15:5–11.

    Article  CAS  PubMed  Google Scholar 

  89. Hyde TM, Gibbs M, Peroutka SJ. (1988) Distribution of muscarinic cholinergic receptors in the dorsal vagal complex and other selected nuclei in the human medulla. Brain Res. 447:287–92.

    Article  CAS  PubMed  Google Scholar 

  90. Lawrence AJ, Jarrot B. (1996) Neurochemical modulation of cardiovascular control in the nucleus tractus solitarius. Prog. Neurobiol. 48:21–53.

    Article  CAS  PubMed  Google Scholar 

  91. Shihara M, Hori N, Hirooka Y, Eshima K, Akaike N, Takeshita A. (1999) Cholinergic system in the nucleus of the solitary tract of rats. Amer. J. Physiol.-Regulat. Integrat. Compar. Physiol. 276:R1141–8.

    Article  CAS  Google Scholar 

  92. Sykes RM, Spyer KM, Izzo PN. (1997) Demonstration of glutamate immunoreactivity in vagal sensory afferents in the nucleus tractus solitarius of the rat. Brain Res. 762:1–11.

    Article  CAS  PubMed  Google Scholar 

  93. Mascarucci P, Perego C, Terrazzino S, De Simoni MG. (1998) Glutamate release in the nucleus tractus solitarius induced by peripheral lipopolysaccharide and interleukin-1β. Neuroscience 86:1285–90.

    Article  CAS  PubMed  Google Scholar 

  94. Hornby P. (2001) Receptors and transmission in the brain-gut axis. II. Excitatory amino acid receptors in the brain-gut axis. Am. J. Physiol.-Gastrointest. Liver Physiol. 280:G1055–60.

    Article  CAS  PubMed  Google Scholar 

  95. Lin LH, Talman WT. (2000) N-methyl-D-aspartate receptors on neurons that synthesize nitric oxide in rat nucleus tractus solitarii. Neuroscience 100:581–8.

    Article  CAS  PubMed  Google Scholar 

  96. Chen C-Y, Bonham AC. (1998) Non-NMDA and NMDA receptors transmit area postrema input to aortic baroreceptor neurons in NTS. Am. J. Physiol.-Heart Circulat. Physiol. 275:H1695–706.

    Article  CAS  Google Scholar 

  97. Ferreira M et al. (2001) Evidence for functional alpha-7 neuronal nicotinic receptor subtype located on motoneurones of the dorsal motor nucleus of the vagus. J. Pharmacol. Exper. Therap. 296:260–9.

    CAS  Google Scholar 

  98. Browning KN, Travagli RA. (2001) Mechanism of action of baclofen in rat dorsal motor nucleus of the vagus. Am. J. Physiol.-Gastrointest. Liver Physiol. 280: G1106–13.

    Article  CAS  PubMed  Google Scholar 

  99. Lewis MW, Travagli RA. (2001) Effects of substance P on identified neurons of the rat dorsal motor nucleus of the vagus. Am. J. Physiol.-Gastrointestin. Liver Physiol. 281:G164–72.

    Article  CAS  Google Scholar 

  100. Blondeau C, Clerc N, Baude A. (2002) Neurokinin-1 and neurokinin-3 receptors are expressed in vagal efferent neurons that innervate different parts of the gastro-intestinal tract. Neuroscience 110:339–49.

    Article  CAS  PubMed  Google Scholar 

  101. Atkinson L, Batten TF, Deuchars J. (2000) P2X(2) receptor immunoreactivity in the dorsal vagal complex and area postrema of the rat. Neuroscience 99:683–96.

    Article  CAS  PubMed  Google Scholar 

  102. Steinlein O. (1998) New functions for nicotine acetylcholine receptors? Behav. Brain Res. 95:31–5.

    Article  CAS  PubMed  Google Scholar 

  103. Marubio LM, Changeux J-P. (2000) Nicotinic acetylcholine receptor knockout mice as animal models for studying receptor function. Eur. J. Pharmacol. 393: 113–21.

    Article  CAS  PubMed  Google Scholar 

  104. Leonard S, Bertrand D. (2001) Neuronal nicotinic receptors: from structure to function. Nicotine Tob. Res. 3:203–23.

    Article  CAS  PubMed  Google Scholar 

  105. Wang H, Yu M, Ochani M, et al. (2003) Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421:384–8.

    Article  CAS  PubMed  Google Scholar 

  106. Orr-Urtreger A et al. (1997) Mice deficient in the α7 neuronal nicotinic acetylcholine receptor lack α-bungarotoxin binding sites and hippocampal fast nicotinic currents. J. Neurosci. 17:9165–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Korach M et al. (2001) Cardiac variability in critically ill adults: Influence of sepsis. Crit. Care Med. 29:1380–5.

    Article  CAS  PubMed  Google Scholar 

  108. Winchell RJ, Hoyt DB. (1996) Spectral analysis of heart rate variability in the ICU: a measure of autonomic function. J. Surg. Res. 63:11–6.

    Article  CAS  PubMed  Google Scholar 

  109. Chensue SW, Terebuh PD, Remick DG, Scales WE, Kunkel SL. (1991) In vivo biological and immunohistochemical analysis of interleukin-1 α, β and tumor necrosis factor during experimental endotoxemia. Am. J. Pathol. 138:395–402.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Honzikova N, Semrad B, Fiser B, Labrova R. (2000) Baroreflex sensitivity determined by spectral method and heart rate variability, and two-years mortality in patients after myocardial infarction. Physiol. Res. 49:643–50.

    CAS  PubMed  Google Scholar 

  111. Meldrum DR. (1998) Tumor necrosis factor in the heart. Am. J. Physiol. 274:R577–95.

    Article  CAS  PubMed  Google Scholar 

  112. Torre-Amione G, Kapadia S, Lee J, Bies RD, Lebovitz R, Mann DL. (1995) Expression and functional significance of tumor necrosis factor receptors in human myocardium. Circulation 92:1487–93.

    Article  CAS  PubMed  Google Scholar 

  113. George MS et al. (2000) Vagus nerve stimulation: a new tool for brain research and therapy. Biol. Psychiatry 47:287–95.

    Article  CAS  PubMed  Google Scholar 

  114. Valencia I, Holder DL, Helmers SL, Madsen JR, Riviello JJ. (2001) Vagus nerve stimulation in pediatric epilepsy: a review. Pediatr. Neurol. 25:368–76.

    Article  CAS  PubMed  Google Scholar 

  115. George MS et al. (2000) Vagus nerve stimulation. A potential therapy for resistant depression? Psychiatr. Clin. North Am. 23:757–83.

    Article  CAS  PubMed  Google Scholar 

  116. Handforth A et al. (1998) Vagus nerve stimulation therapy for partial-onset seizures: A randomized active-control trial. Neurology 51:48–55.

    Article  CAS  PubMed  Google Scholar 

  117. Krahl SE, Clark KB, Smith DC, Browning RA. (1998) Locus coeroleus lesions suppress the seizure attenuating effects of vagus nerve stimulation. Epilepsia 39:709–14.

    Article  CAS  PubMed  Google Scholar 

  118. Naritoku DK, Terry WJ, Helfert RH. (1995) Regional induction of Fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Res. 22:53–62.

    Article  CAS  PubMed  Google Scholar 

  119. Wang H et al. (2002) Nicotine inhibits the release of HMGB1 through post-transcriptional mechanism. Shock 17(S1):62.

    Article  CAS  Google Scholar 

  120. Han JL et al. (2003) Cholinergic suppression of cytokine release from human macrophages. Shock 19(S1):22.

    Article  Google Scholar 

Download references

Acknowledgments

Grant support came from the Dept. of Defense (DARPA) and NIH (NIGMS).

Author information

Authors and Affiliations

  1. Laboratory of Biomedical Science, North Shore LIJ-Research Institute, 350 Community Drive, Manhasset, NY, 11030, USA

    Valentin A. Pavlov, Hong Wang, Christopher J. Czura, Steven G. Friedman & Kevin J. Tracey (Head)

  2. Department of Vascular Surgery, North Shore University Hospital, Manhasset, NY, USA

    Steven G. Friedman

Authors
  1. Valentin A. Pavlov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher J. Czura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steven G. Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kevin J. Tracey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kevin J. Tracey.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pavlov, V.A., Wang, H., Czura, C.J. et al. The Cholinergic Anti-inflammatory Pathway: A Missing Link in Neuroimmunomodulation. Mol Med 9, 125–134 (2003). https://doi.org/10.1007/BF03402177

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03402177

Keywords

Search

Navigation