Skip to main content
SpringerLink
Log in

Immunomodulation by Vasoactive Intestinal Polypeptide (VIP)

  • Chapter
  • First Online:
Neuro-Immuno-Gastroenterology

Abstract

Vasoactive intestinal peptide (VIP) is one of the major neuropeptides expressed and produced by the enteric nervous system. VIP release in the proximity of GI resident immune cells facilitates its immunoregulatory functions, including effects on macrophages, dendritic cells, and T lymphocytes. Here we discuss the functions of VIP as a modulator and possible therapeutic target in gastrointestinal inflammation in the larger context of its general immunoregulatory role.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

APC:

Antigen-presenting cell

CD:

Crohn’s disease

CIA:

Collagen-induced arthritis

CLP:

Cecal ligation and puncture

CNS:

Central nervous system

DC:

Dendritic cell

DSS:

Dextran sodium sulfate

EAE:

Experimental autoimmune encephalomyelitis

ENS:

Enteric nervous system

GI Tract:

Gastrointestinal tract

HMGB1:

High mobility group B1

IBD:

Inflammatory bowel disease

LN:

Lymph node

MS:

Multiple sclerosis

RA:

Retinoic acid

tDC:

Tolerogenic dendritic cells

TLR:

Toll-like receptor

TNBS:

Trinitrobenzene sulfonic acid

UC:

Ulcerative colitis

VIP:

Vasoactive intestinal peptide

References

  1. Chandrasekharan B, Nezami BG, Srinivasan S. Emerging neuropeptide targets in inflammation: NPY and VIP. Am J Physiol Gastrointest Liver Physiol. 2013;304:G949–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Margolis KG, Gershon MD. Neuropeptides and inflammatory bowel disease. Curr Opin Gastroenterol. 2009;25:503–11.

    Article  CAS  PubMed  Google Scholar 

  3. Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR, Vaudry D, Vaudry H, Waschek JA, Said SI. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: Iuphar review 1. Br J Pharmacol. 2012;166:4–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Furness JB. Types of neurons in the enteric nervous system. J Auton Nerv Syst. 2000;81:87–96.

    Article  CAS  PubMed  Google Scholar 

  5. Banks MR, Farthing MJ, Robberecht P, Burleigh DE. Antisecretory actions of a novel vasoactive intestinal polypeptide (vip) antagonist in human and rat small intestine. Br J Pharmacol. 2005;144:994–1001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cooke HJ. Neurotransmitters in neuronal reflexes regulating intestinal secretion. Ann N Y Acad Sci. 2000;915:77–80.

    Article  CAS  PubMed  Google Scholar 

  7. Fung C, Unterweger P, Parry LJ, Bornstein JC, Foong JP. Vpac1 receptors regulate intestinal secretion and muscle contractility by activating cholinergic neurons in guinea pig jejunum. Am J Physiol Gastrointest Liver Physiol. 2014;306:G748–58.

    Article  CAS  PubMed  Google Scholar 

  8. Katsoulis S, Schmidt WE, Clemens A, Schworer H, Creutzfeldt W. Vasoactive intestinal polypeptide induces neurogenic contraction of guinea-pig ileum. Involvement of acetylcholine and substance p. Regul Pept. 1992;38:155–64.

    Article  CAS  PubMed  Google Scholar 

  9. Reddix R, Kuhawara A, Wallace L, Cooke HJ. Vasoactive intestinal polypeptide: a transmitter in submucous neurons mediating secretion in guinea pig distal colon. J Pharmacol Exp Ther. 1994;269:1124–9.

    CAS  PubMed  Google Scholar 

  10. Shi XZ, Sarna SK. Gene therapy of cav1.2 channel with vip and vip receptor agonists and antagonists: a novel approach to designing promotility and antimotility agents. Am J Physiol Gastrointest Liver Physiol. 2008;295:G187–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lelievre V, Favrais G, Abad C, Adle-Biassette H, Lu Y, Germano PM, Cheung-Lau G, Pisegna JR, Gressens P, Lawson G, Waschek JA. Gastrointestinal dysfunction in mice with a targeted mutation in the gene encoding vasoactive intestinal polypeptide: a model for the study of intestinal ileus and hirschsprung’s disease. Peptides. 2007;28:1688–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Holland PW, Garcia-Fernandez J, Williams NA, Sidow A. Gene duplications and the origins of vertebrate development. Dev Suppl. 1994;125–133.

    Google Scholar 

  13. Hoyle CH. Neuropeptide families: evolutionary perspectives. Regul Pept. 1998;73:1–33.

    Article  CAS  PubMed  Google Scholar 

  14. Du BH, Eng J, Hulmes JD, Chang M, Pan YC, Yalow RS. Guinea pig has a unique mammalian vip. Biochem Biophys Res Commun. 1985;128:1093–8.

    Article  CAS  PubMed  Google Scholar 

  15. Foster N. Editorial: vasoactive intestinal peptide (vip): historic perspective and future potential. Endocr Metab Immune Disord Drug Targets. 2012;12:303–7.

    Article  CAS  PubMed  Google Scholar 

  16. Henning RJ, Sawmiller DR. Vasoactive intestinal peptide: cardiovascular effects. Cardiovasc Res. 2001;49:27–37.

    Article  CAS  PubMed  Google Scholar 

  17. Bellinger DL, Lorton D, Horn L, Brouxhon S, Felten SY, Felten DL. Vasoactive intestinal polypeptide (vip) innervation of rat spleen, thymus, and lymph nodes. Peptides. 1997;18:1139–49.

    Article  CAS  PubMed  Google Scholar 

  18. Ganea D, Hooper KM, Kong W. The neuropeptide vasoactive intestinal peptide: direct effects on immune cells and involvement in inflammatory and autoimmune diseases. Acta Physiol (Oxf). 2014.

    Google Scholar 

  19. Leceta J, Martinez MC, Delgado M, Garrido E, Gomariz RP. Lymphoid cell subpopulations containing vasoactive intestinal peptide in the rat. Peptides. 1994;15:791–7.

    Article  CAS  PubMed  Google Scholar 

  20. Delgado M, Ganea D. Cutting edge: is vasoactive intestinal peptide a type 2 cytokine? J Immunol. 2001;166:2907–12.

    Article  CAS  PubMed  Google Scholar 

  21. Voice JK, Grinninger C, Kong Y, Bangale Y, Paul S, Goetzl EJ. Roles of vasoactive intestinal peptide (vip) in the expression of different immune phenotypes by wild-type mice and t cell-targeted type ii vip receptor transgenic mice. J Immunol. 2003;170:308–14.

    Article  CAS  PubMed  Google Scholar 

  22. Li JM, Southerland L, Hossain MS, Giver CR, Wang Y, Darlak K, Harris W, Waschek J, Waller EK. Absence of vasoactive intestinal peptide expression in hematopoietic cells enhances th1 polarization and antiviral immunity in mice. J Immunol. 2011;187:1057–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Andersen O, Fahrenkrug J, Wikkelso C, Johansson BB. Vip in cerebrospinal fluid of patients with multiple sclerosis. Peptides. 1984;5:435–7.

    Article  CAS  PubMed  Google Scholar 

  24. Martinez C, Ortiz AM, Juarranz Y, Lamana A, Seoane IV, Leceta J, Garcia-Vicuna R, Gomariz RP, Gonzalez-Alvaro I. Serum levels of vasoactive intestinal peptide as a prognostic marker in early arthritis. PLoS One. 2014;9:e85248.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Tornwall J, Uusitalo H, Hukkanen M, Sorsa T, Konttinen YT. Distribution of vasoactive intestinal peptide (vip) and its binding sites in labial salivary glands in sjogren’s syndrome and in normal controls. Clin Exp Rheumatol. 1994;12:287–92.

    CAS  PubMed  Google Scholar 

  26. Bangale Y, Karle S, Planque S, Zhou YX, Taguchi H, Nishiyama Y, Li L, Kalaga R, Paul S. Vipase autoantibodies in fas-defective mice and patients with autoimmune disease. FASEB J. 2003;17:628–35.

    Article  CAS  PubMed  Google Scholar 

  27. Bishop AE, Polak JM, Bryant MG, Bloom SR, Hamilton S. Abnormalities of vasoactive intestinal polypeptide-containing nerves in crohn’s disease. Gastroenterology. 1980;79:853–60.

    CAS  PubMed  Google Scholar 

  28. O’Morain C, Bishop AE, McGregor GP, Levi AJ, Bloom SR, Polak JM, Peters TJ. Vasoactive intestinal peptide concentrations and immunocytochemical studies in rectal biopsies from patients with inflammatory bowel disease. Gut. 1984;25:57–61.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Schneider J, Jehle EC, Starlinger MJ, Neunlist M, Michel K, Hoppe S, Schemann M. Neurotransmitter coding of enteric neurones in the submucous plexus is changed in non-inflamed rectum of patients with crohn’s disease. Neurogastroenterol Motil. 2001;13:255–64.

    Article  CAS  PubMed  Google Scholar 

  30. Kimura M, Masuda T, Hiwatashi N, Toyota T, Nagura H. Changes in neuropeptide-containing nerves in human colonic mucosa with inflammatory bowel disease. Pathol Int. 1994;44:624–34.

    Article  CAS  PubMed  Google Scholar 

  31. Kubota Y, Petras RE, Ottaway CA, Tubbs RR, Farmer RG, Fiocchi C. Colonic vasoactive intestinal peptide nerves in inflammatory bowel disease. Gastroenterology. 1992;102:1242–51.

    CAS  PubMed  Google Scholar 

  32. Baticic L, Detel D, Kucic N, Buljevic S, Pugel EP, Varljen J. Neuroimmunomodulative properties of dipeptidyl peptidase iv/cd26 in a tnbs-induced model of colitis in mice. J Cell Biochem. 2011;112:3322–33.

    Article  CAS  PubMed  Google Scholar 

  33. Sigalet DL, Wallace L, De Heuval E, Sharkey KA. The effects of glucagon-like peptide 2 on enteric neurons in intestinal inflammation. Neurogastroenterol Motil. 2010;22:1318–e1350.

    Article  CAS  PubMed  Google Scholar 

  34. Abad C, Gomariz R, Waschek J, Leceta J, Martinez C, Juarranz Y, Arranz A. Vip in inflammatory bowel disease: state of the art. Endocr Metab Immune Disord Drug Targets. 2012;12:316–22.

    Article  CAS  PubMed  Google Scholar 

  35. Reubi JC. In vitro evaluation of vip/pacap receptors in healthy and diseased human tissues. Clinical implications. Ann N Y Acad Sci. 2000;921:1–25.

    Article  CAS  PubMed  Google Scholar 

  36. Usdin TB, Bonner TI, Mezey E. Two receptors for vasoactive intestinal polypeptide with similar specificity and complementary distributions. Endocrinology. 1994;135:2662–80.

    CAS  PubMed  Google Scholar 

  37. Vaudry D, Gonzalez BJ, Basille M, Yon L, Fournier A, Vaudry H. Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol Rev. 2000;52:269–324.

    CAS  PubMed  Google Scholar 

  38. Couvineau A, Laburthe M. Vpac receptors: structure, molecular pharmacology and interaction with accessory proteins. Br J Pharmacol. 2012;166:42–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Delgado M, Pozo D, Ganea D. The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev. 2004;56:249–90.

    Article  CAS  PubMed  Google Scholar 

  40. Delgado M, Ganea D. Anti-inflammatory neuropeptides: a new class of endogenous immunoregulatory agents. Brain Behav Immun. 2008;22:1146–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gonzalez-Rey E, Delgado M. Anti-inflammatory neuropeptide receptors: new therapeutic targets for immune disorders? Trends Pharmacol Sci. 2007;28:482–91.

    Article  CAS  PubMed  Google Scholar 

  42. Delgado M, Robledo G, Rueda B, Varela N, O’Valle F, Hernandez-Cortes P, Caro M, Orozco G, Gonzalez-Rey E, Martin J. Genetic association of vasoactive intestinal peptide receptor with rheumatoid arthritis: altered expression and signal in immune cells. Arthritis Rheum. 2008;58:1010–9.

    Article  CAS  PubMed  Google Scholar 

  43. Juarranz Y, Gutierrez-Canas I, Santiago B, Carrion M, Pablos JL, Gomariz RP. Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts. Arthritis Rheum. 2008;58:1086–95.

    Article  CAS  PubMed  Google Scholar 

  44. Paladini F, Cocco E, Cauli A, Cascino I, Vacca A, Belfiore F, Fiorillo MT, Mathieu A, Sorrentino R. A functional polymorphism of the vasoactive intestinal peptide receptor 1 gene correlates with the presence of hla-b*2705 in sardinia. Genes Immun. 2008;9:659–67.

    Article  CAS  PubMed  Google Scholar 

  45. Sun W, Hong J, Zang YC, Liu X, Zhang JZ. Altered expression of vasoactive intestinal peptide receptors in t lymphocytes and aberrant th1 immunity in multiple sclerosis. Int Immunol. 2006;18:1691–700.

    Article  CAS  PubMed  Google Scholar 

  46. Hauk V, Fraccaroli L, Grasso E, Eimon A, Ramhorst R, Hubscher O, Perez Leiros C. Monocytes from sjogren’s syndrome patients display increased vasoactive intestinal peptide receptor 2 expression and impaired apoptotic cell phagocytosis. Clin Exp Immunol. 2014;177:662–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Harmar AJ, Arimura A, Gozes I, Journot L, Laburthe M, Pisegna JR, Rawlings SR, Robberecht P, Said SI, Sreedharan SP, Wank SA, Waschek JA. International union of pharmacology. Xviii. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol Rev. 1998;50:265–70.

    CAS  PubMed  Google Scholar 

  48. Massacand JC, Kaiser P, Ernst B, Tardivel A, Burki K, Schneider P, Harris NL. Intestinal bacteria condition dendritic cells to promote iga production. PLoS One. 2008;3:e2588.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Delgado M, Chorny A, Gonzalez-Rey E, Ganea D. Vasoactive intestinal peptide generates cd4 + cd25+ regulatory t cells in vivo. J Leukoc Biol. 2005;78:1327–38.

    Article  CAS  PubMed  Google Scholar 

  50. Delgado M, Gonzalez-Rey E, Ganea D. The neuropeptide vasoactive intestinal peptide generates tolerogenic dendritic cells. J Immunol. 2005;175:7311–24.

    Article  CAS  PubMed  Google Scholar 

  51. Yukawa T, Oshitani N, Yamagami H, Watanabe K, Higuchi K, Arakawa T. Differential expression of vasoactive intestinal peptide receptor 1 expression in inflammatory bowel disease. Int J Mol Med. 2007;20:161–7.

    CAS  PubMed  Google Scholar 

  52. Burian B, Storka A, Marzluf BA, Yen YC, Lambers C, Robibaro B, Vonbank K, Mosgoeller W, Petkov V. Vasoactive intestinal peptide (vip) receptor expression in monocyte-derived macrophages from copd patients. Peptides. 2010;31:603–8.

    Article  CAS  PubMed  Google Scholar 

  53. Kawashima K, Yoshikawa K, Fujii YX, Moriwaki Y, Misawa H. Expression and function of genes encoding cholinergic components in murine immune cells. Life Sci. 2007;80:2314–9.

    Article  CAS  PubMed  Google Scholar 

  54. Leceta J, Gomariz RP, Martinez C, Abad C, Ganea D, Delgado M. Receptors and transcriptional factors involved in the anti-inflammatory activity of vip and pacap. Ann N Y Acad Sci. 2000;921:92–102.

    Article  CAS  PubMed  Google Scholar 

  55. Chorny A, Delgado M. Neuropeptides rescue mice from lethal sepsis by down-regulating secretion of the late-acting inflammatory mediator high mobility group box 1. Am J Pathol. 2008;172:1297–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Arranz A, Juarranz Y, Leceta J, Gomariz RP, Martinez C. Vip balances innate and adaptive immune responses induced by specific stimulation of tlr2 and tlr4. Peptides. 2008;29:948–56.

    Article  CAS  PubMed  Google Scholar 

  57. Foster N, Lea SR, Preshaw PM, Taylor JJ. Pivotal advance: vasoactive intestinal peptide inhibits up-regulation of human monocyte tlr2 and tlr4 by lps and differentiation of monocytes to macrophages. J Leukoc Biol. 2007;81:893–903.

    Article  CAS  PubMed  Google Scholar 

  58. Gomariz RP, Arranz A, Abad C, Torroba M, Martinez C, Rosignoli F, Garcia-Gomez M, Leceta J, Juarranz Y. Time-course expression of toll-like receptors 2 and 4 in inflammatory bowel disease and homeostatic effect of vip. J Leukoc Biol. 2005;78:491–502.

    Article  CAS  PubMed  Google Scholar 

  59. Gutierrez-Canas I, Juarranz Y, Santiago B, Arranz A, Martinez C, Galindo M, Paya M, Gomariz RP, Pablos JL. Vip down-regulates tlr4 expression and tlr4-mediated chemokine production in human rheumatoid synovial fibroblasts. Rheumatology (Oxford). 2006;45:527–32.

    Article  CAS  Google Scholar 

  60. Delgado M, Ganea D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit nuclear factor-kappa b-dependent gene activation at multiple levels in the human monocytic cell line thp-1. J Biol Chem. 2001;276:369–80.

    Article  CAS  PubMed  Google Scholar 

  61. Delgado M, Ganea D. Inhibition of ifn-gamma-induced janus kinase-1-stat1 activation in macrophages by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. J Immunol. 2000;165:3051–7.

    Article  CAS  PubMed  Google Scholar 

  62. Delgado M, Munoz-Elias EJ, Kan Y, Gozes I, Fridkin M, Brenneman DE, Gomariz RP, Ganea D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit tumor necrosis factor alpha transcriptional activation by regulating nuclear factor-kb and camp response element-binding protein/c-jun. J Biol Chem. 1998;273:31427–36.

    Article  CAS  PubMed  Google Scholar 

  63. Delgado M. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the mekk1/mek4/jnk signaling pathway in endotoxin-activated microglia. Biochem Biophys Res Commun. 2002;293:771–6.

    Article  CAS  PubMed  Google Scholar 

  64. Maldonado RA, von Andrian UH. How tolerogenic dendritic cells induce regulatory t cells. Adv Immunol. 2010;108:111–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chorny A, Gonzalez-Rey E, Fernandez-Martin A, Pozo D, Ganea D, Delgado M. Vasoactive intestinal peptide induces regulatory dendritic cells with therapeutic effects on autoimmune disorders. Proc Natl Acad Sci U S A. 2005;102:13562–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chorny A, Gonzalez-Rey E, Fernandez-Martin A, Ganea D, Delgado M. Vasoactive intestinal peptide induces regulatory dendritic cells that prevent acute graft-versus-host disease while maintaining the graft-versus-tumor response. Blood. 2006;107:3787–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Toscano MG, Delgado M, Kong W, Martin F, Skarica M, Ganea D. Dendritic cells transduced with lentiviral vectors expressing vip differentiate into vip-secreting tolerogenic-like dcs. Mol Ther. 2010;18:1035–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol. 2003;3:331–41.

    Article  CAS  PubMed  Google Scholar 

  69. Ruane DT, Lavelle EC. The role of cd103(+) dendritic cells in the intestinal mucosal immune system. Front Immunol. 2011;2:25.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Scott CL, Aumeunier AM, Mowat AM. Intestinal cd103+ dendritic cells: master regulators of tolerance? Trends Immunol. 2011;32:412–9.

    Article  CAS  PubMed  Google Scholar 

  71. Scott CL, Bain CC, Wright PB, Sichien D, Kotarsky K, Persson EK, Luda K, Guilliams M, Lambrecht BN, Agace WW, Milling SW, Mowat AM. Ccr2cd103 intestinal dendritic cells develop from dc-committed precursors and induce interleukin-17 production by t cells. Mucosal Immunol. 2015;8:327–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mazzini E, Massimiliano L, Penna G, Rescigno M. Oral tolerance can be established via gap junction transfer of fed antigens from cx3cr1(+) macrophages to cd103(+) dendritic cells. Immunity. 2014;40:248–61.

    Article  CAS  PubMed  Google Scholar 

  73. Schulz O, Jaensson E, Persson EK, Liu X, Worbs T, Agace WW, Pabst O. Intestinal cd103+, but not cx3cr1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J Exp Med. 2009;206:3101–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Delgado M, Reduta A, Sharma V, Ganea D. Vip/pacap oppositely affects immature and mature dendritic cell expression of cd80/cd86 and the stimulatory activity for cd4(+) t cells. J Leukoc Biol. 2004;75:1122–30.

    Article  CAS  PubMed  Google Scholar 

  75. Delgado M, Sun W, Leceta J, Ganea D. Vip and pacap differentially regulate the costimulatory activity of resting and activated macrophages through the modulation of b7.1 and b7.2 expression. J Immunol. 1999;163:4213–23.

    CAS  PubMed  Google Scholar 

  76. Ganea D, Rodriguez R, Delgado M. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: players in innate and adaptive immunity. Cell Mol Biol (Noisy-le-Grand). 2003;49:127–42.

    CAS  Google Scholar 

  77. Liu L, Yen JH, Ganea D. A novel vip signaling pathway in t cells camp--> protein tyrosine phosphatase (shp-2?)--> jak2/stat4--> th1 differentiation. Peptides. 2007;28:1814–24.

    Google Scholar 

  78. Voice J, Donnelly S, Dorsam G, Dolganov G, Paul S, Goetzl EJ. C-maf and junb mediation of th2 differentiation induced by the type 2 g protein-coupled receptor (vpac2) for vasoactive intestinal peptide. J Immunol. 2004;172:7289–96.

    Article  CAS  PubMed  Google Scholar 

  79. Delgado M, Leceta J, Ganea D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide promote in vivo generation of memory th2 cells. FASEB J. 2002;16:1844–6.

    CAS  PubMed  Google Scholar 

  80. Sharma V, Delgado M, Ganea D. Granzyme b, a new player in activation-induced cell death, is down-regulated by vasoactive intestinal peptide in th2 but not th1 effectors. J Immunol. 2006;176:97–110.

    Article  CAS  PubMed  Google Scholar 

  81. Goetzl EJ, Voice JK, Shen S, Dorsam G, Kong Y, West KM, Morrison CF, Harmar AJ. Enhanced delayed-type hypersensitivity and diminished immediate-type hypersensitivity in mice lacking the inducible vpac(2) receptor for vasoactive intestinal peptide. Proc Natl Acad Sci U S A. 2001;98:13854–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Voice JK, Dorsam G, Lee H, Kong Y, Goetzl EJ. Allergic diathesis in transgenic mice with constitutive t cell expression of inducible vasoactive intestinal peptide receptor. FASEB J. 2001;15:2489–96.

    Article  CAS  PubMed  Google Scholar 

  83. Bovenschen HJ, van de Kerkhof PC, van Erp PE, Woestenenk R, Joosten I, Koenen HJ. Foxp3+ regulatory t cells of psoriasis patients easily differentiate into il-17a-producing cells and are found in lesional skin. J Invest Dermatol. 2011;131:1853–60.

    Article  CAS  PubMed  Google Scholar 

  84. Ferraccioli G, Zizzo G. The potential role of th17 in mediating the transition from acute to chronic autoimmune inflammation: rheumatoid arthritis as a model. Discov Med. 2011;11:413–24.

    PubMed  Google Scholar 

  85. Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, Bamba T, Fujiyama Y. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003;52:65–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N, Becher B, Prat A. Human th17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation. Nat Med. 2007;13:1173–5.

    Article  CAS  PubMed  Google Scholar 

  87. Jimeno R, Gomariz RP, Gutierrez-Canas I, Martinez C, Juarranz Y, Leceta J. New insights into the role of vip on the ratio of t-cell subsets during the development of autoimmune diabetes. Immunol Cell Biol. 2010;88:734–45.

    Article  CAS  PubMed  Google Scholar 

  88. Deng S, Xi Y, Wang H, Hao J, Niu X, Li W, Tao Y, Chen G. Regulatory effect of vasoactive intestinal peptide on the balance of treg and th17 in collagen-induced arthritis. Cell Immunol. 2010;265:105–10.

    Article  CAS  PubMed  Google Scholar 

  89. Ding W, Manni M, Stohl LL, Zhou XK, Wagner JA, Granstein RD. Pituitary adenylate cyclase-activating peptide and vasoactive intestinal polypeptide bias langerhans cell ag presentation toward th17 cells. Eur J Immunol. 2012;42:901–11.

    Article  CAS  PubMed  Google Scholar 

  90. Yadav M, Rosenbaum J, Goetzl EJ. Cutting edge: vasoactive intestinal peptide (vip) induces differentiation of th17 cells with a distinctive cytokine profile. J Immunol. 2008;180:2772–6.

    Article  CAS  PubMed  Google Scholar 

  91. Jimeno R, Leceta J, Martinez C, Gutierrez-Canas I, Carrion M, Perez-Garcia S, Garin M, Mellado M, Gomariz RP, Juarranz Y. Vasoactive intestinal peptide maintains the nonpathogenic profile of human th17-polarized cells. J Mol Neurosci. 2014;54:512–25.

    Article  CAS  PubMed  Google Scholar 

  92. Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, Sobel RA, Regev A, Kuchroo VK. Induction and molecular signature of pathogenic th17 cells. Nat Immunol. 2012;13:991–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Prasse A, Zissel G, Lutzen N, Schupp J, Schmiedlin R, Gonzalez-Rey E, Rensing-Ehl A, Bacher G, Cavalli V, Bevec D, Delgado M, Muller-Quernheim J. Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. Am J Respir Crit Care Med. 2010;182:540–8.

    Article  CAS  PubMed  Google Scholar 

  94. Chen G, Hao J, Xi Y, Wang W, Wang Z, Li N, Li W. The therapeutic effect of vasoactive intestinal peptide on experimental arthritis is associated with cd4 + cd25+ t regulatory cells. Scand J Immunol. 2008;68:572–8.

    Article  CAS  PubMed  Google Scholar 

  95. Fernandez-Martin A, Gonzalez-Rey E, Chorny A, Martin J, Pozo D, Ganea D, Delgado M. Vip prevents experimental multiple sclerosis by downregulating both inflammatory and autoimmune components of the disease. Ann N Y Acad Sci. 2006;1070:276–81.

    Article  CAS  PubMed  Google Scholar 

  96. Gonzalez-Rey E, Fernandez-Martin A, Chorny A, Delgado M. Vasoactive intestinal peptide induces cd4+, cd25+ t regulatory cells with therapeutic effect in collagen-induced arthritis. Arthritis Rheum. 2006;54:864–76.

    Article  CAS  PubMed  Google Scholar 

  97. Delgado M, Toscano MG, Benabdellah K, Cobo M, O’Valle F, Gonzalez-Rey E, Martin F. In vivo delivery of lentiviral vectors expressing vasoactive intestinal peptide complementary DNA as gene therapy for collagen-induced arthritis. Arthritis Rheum. 2008;58:1026–37.

    Article  CAS  PubMed  Google Scholar 

  98. DMaG D. Vasoactive intestinal peptide: immune mediator and potential therapeutic agent. In: Levite M, editor. Nerve-driven immunity. Wien: Springer; 2012. p. 257–89.

    Google Scholar 

  99. Cauwels A, Brouckaert P. Nitrite regulation of shock. Cardiovasc Res. 2011;89:553–9.

    Article  CAS  PubMed  Google Scholar 

  100. Remick DG, Bolgos G, Copeland S, Siddiqui J. Role of interleukin-6 in mortality from and physiologic response to sepsis. Infect Immun. 2005;73:2751–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tang H, Ivanciu L, Popescu N, Peer G, Hack E, Lupu C, Taylor Jr FB, Lupu F. Sepsis-induced coagulation in the baboon lung is associated with decreased tissue factor pathway inhibitor. Am J Pathol. 2007;171:1066–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ulloa L, Tracey KJ. The “cytokine profile”: a code for sepsis. Trends Mol Med. 2005;11:56–63.

    Article  CAS  PubMed  Google Scholar 

  103. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ. Hmg-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285:248–51.

    Article  CAS  PubMed  Google Scholar 

  104. Fink MP. Animal models of sepsis. Virulence. 2014;5:143–53.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Unsinger J, McDonough JS, Shultz LD, Ferguson TA, Hotchkiss RS. Sepsis-induced human lymphocyte apoptosis and cytokine production in “humanized” mice. J Leukoc Biol. 2009;86:219–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ibrahim H, Barrow P, Foster N. Vip as a potential therapeutic agent in gram negative sepsis. Endocr Metab Immune Disord Drug Targets. 2012;12:308–15.

    Article  CAS  PubMed  Google Scholar 

  107. Delgado M, Gomariz RP, Martinez C, Abad C, Leceta J. Anti-inflammatory properties of the type 1 and type 2 vasoactive intestinal peptide receptors: role in lethal endotoxic shock. Eur J Immunol. 2000;30:3236–46.

    Article  CAS  PubMed  Google Scholar 

  108. Delgado M, Martinez C, Pozo D, Calvo JR, Leceta J, Ganea D, Gomariz RP. Vasoactive intestinal peptide (vip) and pituitary adenylate cyclase-activation polypeptide (pacap) protect mice from lethal endotoxemia through the inhibition of tnf-alpha and il-6. J Immunol. 1999;162:1200–5.

    CAS  PubMed  Google Scholar 

  109. Martinez C, Abad C, Delgado M, Arranz A, Juarranz MG, Rodriguez-Henche N, Brabet P, Leceta J, Gomariz RP. Anti-inflammatory role in septic shock of pituitary adenylate cyclase-activating polypeptide receptor. Proc Natl Acad Sci U S A. 2002;99:1053–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Martinez C, Juarranz Y, Abad C, Arranz A, Miguel BG, Rosignoli F, Leceta J, Gomariz RP. Analysis of the role of the pac1 receptor in neutrophil recruitment, acute-phase response, and nitric oxide production in septic shock. J Leukoc Biol. 2005;77:729–38.

    Article  CAS  PubMed  Google Scholar 

  111. Abad C, Tan YV, Cheung-Lau G, Nobuta H, Waschek JA. Vip deficient mice exhibit resistance to lipopolysaccharide induced endotoxemia with an intrinsic defect in proinflammatory cellular responses. PLoS One. 2012;7:e36922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 2009;30:475–87.

    Article  CAS  PubMed  Google Scholar 

  113. Goyal N, Rana A, Ahlawat A, Bijjem KR, Kumar P. Animal models of inflammatory bowel disease: a review. Inflammopharmacology. 2014;22:219–33.

    Article  PubMed  Google Scholar 

  114. Randhawa PK, Singh K, Singh N, Jaggi AS. A review on chemical-induced inflammatory bowel disease models in rodents. Korean J Physiol Pharmacol. 2014;18:279–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Abad C, Juarranz Y, Martinez C, Arranz A, Rosignoli F, Garcia-Gomez M, Leceta J, Gomariz RP. Cdna array analysis of cytokines, chemokines, and receptors involved in the development of tnbs-induced colitis: homeostatic role of vip. Inflamm Bowel Dis. 2005;11:674–84.

    Article  PubMed  Google Scholar 

  116. Abad C, Martinez C, Juarranz MG, Arranz A, Leceta J, Delgado M, Gomariz RP. Therapeutic effects of vasoactive intestinal peptide in the trinitrobenzene sulfonic acid mice model of crohn’s disease. Gastroenterology. 2003;124:961–71.

    Article  CAS  PubMed  Google Scholar 

  117. Arranz A, Abad C, Juarranz Y, Leceta J, Martinez C, Gomariz RP. Vasoactive intestinal peptide as a healing mediator in crohn’s disease. Neuroimmunomodulation. 2008;15:46–53.

    CAS  PubMed  Google Scholar 

  118. Arranz A, Abad C, Juarranz Y, Torroba M, Rosignoli F, Leceta J, Gomariz RP, Martinez C. Effect of vip on tlr2 and tlr4 expression in lymph node immune cells during tnbs-induced colitis. Ann N Y Acad Sci. 2006;1070:129–34.

    Article  CAS  PubMed  Google Scholar 

  119. Abad C, Cheung-Lau G, Coute-Monvoisin AC, Waschek JA. Vasoactive intestinal peptide-deficient mice exhibit reduced pathology in trinitrobenzene sulfonic acid-induced colitis. Neuroimmunomodulation. 2015;22:203–12.

    Google Scholar 

  120. Newman R, Cuan N, Hampartzoumian T, Connor SJ, Lloyd AR, Grimm MC. Vasoactive intestinal peptide impairs leucocyte migration but fails to modify experimental murine colitis. Clin Exp Immunol. 2005;139:411–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Vu JP, Million M, Larauche M, Luong L, Norris J, Waschek JA, Pothoulakis C, Pisegna JR, Germano PM. Inhibition of vasoactive intestinal polypeptide (vip) induces resistance to dextran sodium sulfate (dss)-induced colitis in mice. J Mol Neurosci. 2014;52:37–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tan YV, Abad C, Wang Y, Lopez R, Waschek JA. Vpac2 (vasoactive intestinal peptide receptor type 2) receptor deficient mice develop exacerbated experimental autoimmune encephalomyelitis with increased th1/th17 and reduced th2/treg responses. Brain Behav Immun. 2015;44:167–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Delgado M, Ganea D. Inhibition of endotoxin-induced macrophage chemokine production by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide in vitro and in vivo. J Immunol. 2001;167:966–75.

    Article  CAS  PubMed  Google Scholar 

  124. Delgado M, Leceta J, Ganea D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the production of inflammatory mediators by activated microglia. J Leukoc Biol. 2003;73:155–64.

    Article  CAS  PubMed  Google Scholar 

  125. Delgado M, Munoz-Elias EJ, Gomariz RP, Ganea D. Vip and pacap inhibit il-12 production in lps-stimulated macrophages. Subsequent effect on ifngamma synthesis by t cells. J Neuroimmunol. 1999;96:167–81.

    Article  CAS  PubMed  Google Scholar 

  126. Yadav M, Huang MC, Goetzl EJ. Vpac1 (vasoactive intestinal peptide (vip) receptor type 1) g protein-coupled receptor mediation of vip enhancement of murine experimental colitis. Cell Immunol. 2011;267:124–32.

    Article  CAS  PubMed  Google Scholar 

  127. Kremer B, Mariman R, van Erk M, Lagerweij T, Nagelkerken L. Temporal colonic gene expression profiling in the recurrent colitis model identifies early and chronic inflammatory processes. PLoS One. 2012;7:e50388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Abad C, Tan YV, Lopez R, Nobuta H, Dong H, Phan P, Feng JM, Campagnoni AT, Waschek JA. Vasoactive intestinal peptide loss leads to impaired cns parenchymal t-cell infiltration and resistance to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2010;107:19555–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Leuchte HH, Baezner C, Baumgartner RA, Bevec D, Bacher G, Neurohr C, Behr J. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J. 2008;32:1289–94.

    Article  CAS  PubMed  Google Scholar 

  130. Gonzalez-Rey E, Ganea D, Delgado M. Neuropeptides: keeping the balance between pathogen immunity and immune tolerance. Curr Opin Pharmacol. 2010;10:473–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Azuma YT, Hagi K, Shintani N, Kuwamura M, Nakajima H, Hashimoto H, Baba A, Takeuchi T. Pacap provides colonic protection against dextran sodium sulfate induced colitis. J Cell Physiol. 2008;216:111–9.

    Article  CAS  PubMed  Google Scholar 

  132. Nemetz N, Abad C, Lawson G, Nobuta H, Chhith S, Duong L, Tse G, Braun J, Waschek JA. Induction of colitis and rapid development of colorectal tumors in mice deficient in the neuropeptide pacap. Int J Cancer. 2008;122:1803–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Tan YV, Abad C, Lopez R, Dong H, Liu S, Lee A, Gomariz RP, Leceta J, Waschek JA. Pituitary adenylyl cyclase-activating polypeptide is an intrinsic regulator of treg abundance and protects against experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2009;106:2012–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Tan YV, Abad C, Wang Y, Lopez R, Waschek JA. Pituitary adenylate cyclase activating peptide deficient mice exhibit impaired thymic and extrathymic regulatory t cell proliferation during eae. PLoS One. 2013;8:e61200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the NIH/NIAID RO1AI47325 (DG) grant.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Microbiology and Immunology, Temple University Lewis Katz School of Medicine, 3500 N. Broad Street, Philadelphia, PA, USA

    Kirsten M. Hooper MS, PhD, Weimin Kong PhD & Doina Ganea PhD

Authors
  1. Kirsten M. Hooper MS, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weimin Kong PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Doina Ganea PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Doina Ganea PhD .

Editor information

Editors and Affiliations

  1. Neurology, C Floor South Block, University of Nottingham, Nottingham, United Kingdom

    Cris Constantinescu

  2. Atlantic Digestive Health Institute, Morristown Medical Center, Columbus, Ohio, USA

    Razvan Arsenescu

  3. Armedica LLC, Columbus, Ohio, USA

    Violeta Arsenescu

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Hooper, K.M., Kong, W., Ganea, D. (2016). Immunomodulation by Vasoactive Intestinal Polypeptide (VIP). In: Constantinescu, C., Arsenescu, R., Arsenescu, V. (eds) Neuro-Immuno-Gastroenterology. Springer, Cham. https://doi.org/10.1007/978-3-319-28609-9_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-28609-9_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-28607-5

  • Online ISBN: 978-3-319-28609-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation