Skip to main content
SpringerLink
Log in

A Novel Mechanism for Immunosuppression: from Neuropeptides to Regulatory T Cells

  • Invited Review
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Vasoactive intestinal peptide (VIP), a well-known immunoregulatory neuropeptide, affects both innate and adaptive immunity, and acts as a major anti-inflammatory factor in animal models of autoimmune diseases. VIP down-regulates the innate immune response by inhibiting the release of proinflammatory cytokines, chemokines, and nitric oxide by activated macrophages, microglia, and dendritic cells. VIP affects the adaptive immune response by reducing the costimulatory capacity of antigen-presenting cells, and by preferentially inducing Th2-type responses. This is accomplished through preferential Th2 differentiation, enhanced survival of Th2 effectors, and the induction of Th2-attracting chemokines. Recently, we discovered a novel mechanism for the immunosuppressive effect of VIP that involves the generation of antigen-specific regulatory T cells (Treg) through the induction of tolerogenic dendritic cells (tDC). In this work, we review the VIP-induced Treg generation both in vivo and in vitro, and the use of VIP-generated Treg in two models of autoimmunity, i.e., collagen-induced arthritis and experimental autoimmune encephalomyelitis, and in bone marrow transplantation as related to graft-versus-host disease and the graft-versus-leukemia response.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

APC:

antigen presenting cells

BM:

bone marrow

CII:

collagen II

CIA:

collagen-induced arthritis

CNS:

central nervous system

DC:

dendritic cells

DLN:

draining lymph nodes

EAE:

experimental autoimmune encephalomyelitis

GVHD:

graft-versus-host disease

GVL:

graft versus leukemia

IBD:

inflammatory bowel disease

MOG:

myelin/oligodendrocyte glycoprotein

MS:

multiple sclerosis

Nrp-1:

neuropilin 1

OVA:

ovalbumin

PCCF:

pigeon cytochrome c fragment

PLP:

proteolipid protein

RA:

rheumatoid arthritis

tDC:

tolerogenic dendritic cells

TCR:

T cell receptor

Treg:

regulatory T cells

VIP:

vasoactive intestinal peptide

References

  • Abad C, Martinez C, Leceta J, Gomariz RP, Delgado M (2001) Pituitary adenylate cyclase-activating polypeptide inhibits collagen-induced arthritis: an experimental immunomodulatory therapy. J Immunol 167:3182–3189

    PubMed  CAS  Google Scholar 

  • Abad C, Martinez C, Juarranz MG, Arranz A, Leceta J, Delgado M, Gomariz RP (2003) Therapeutic effects of vasoactive intestinal peptide in the trinitrobenzene sulfonic acid mice model of Crohn’s disease. Gastroenterology 124:961–971

    Article  PubMed  CAS  Google Scholar 

  • Abad C, Gomariz RP, Waschek JA (2006) Neuropeptide mimetics and antagonists in the treatment of inflammatory disease: focus on VIP and PACAP. Curr Top Med Chem 6:151–163

    Article  PubMed  CAS  Google Scholar 

  • Bandyopadhyay A, Chakder S, Rattan S (1997) Regulation of inducible and neuronal nitric oxide synthase gene expression by interferon-gamma and VIP. Am J Physiol 272:C1790–1797

    PubMed  CAS  Google Scholar 

  • Chorny A, Gonzalez-Rey E, Fernandez-Martin A, Pozo D, Ganea D, Delgado M (2005) Vasoactive intestinal peptide induces regulatory dendritic cells with therapeutic effects on autoimmune disorders. Proc Natl Acad Sci USA 102:13562–13567

    Article  PubMed  CAS  Google Scholar 

  • Chorny A, Gonzalez-Rey E, Fernandez-Martin A, Ganea D, Delgado M (2006) Vasoactive intestinal peptide induces regulatory dendritic cells that can prevent acute graft-versus-host disease while maintain graft-versus-tumor. Blood 107(9):3787–3794

    Article  PubMed  CAS  Google Scholar 

  • Delgado M, Ganea D (1999) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit interleukin-12 transcription by regulating nuclear factor kappaB and Ets activation. J Biol Chem 274:31930–31940

    Article  PubMed  CAS  Google Scholar 

  • Delgado M, Ganea D (2001a) 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 276:369–380

    Article  PubMed  CAS  Google Scholar 

  • Delgado M, Ganea D (2001b) Inhibition of endotoxin-induced macrophage chemokine production by VIP and PACAP in vitro and in vivo. Arch Physiol Biochem 109:377–382

    PubMed  CAS  Google Scholar 

  • Delgado M, Ganea D (2003a) Vasoactive intestinal peptide inhibits IL-8 production in human monocytes by downregulating nuclear factor kappaB-dependent transcriptional activity. Biochem Biophys Res Commun 302:275–283

    Article  PubMed  CAS  Google Scholar 

  • Delgado M, Ganea D (2003b) Neuroprotective effect of vasoactive intestinal peptide (VIP) in a mouse model of Parkinson’s disease by blocking microglial activation. FASEB J 17:944–946

    PubMed  CAS  Google Scholar 

  • Delgado M, Ganea D (2003c) Vasoactive intestinal peptide prevents activated microglia-induced neurodegeneration under inflammatory conditions: potential therapeutic role in brain trauma. FASEB J 17:1922–1924

    PubMed  CAS  Google Scholar 

  • Delgado M, Munoz-Elias EJ, Kan Y, Gozes I, Fridkin M, Brenneman DE, Gomariz RP, Ganea D (1998) 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 273:31427–31436

    Article  PubMed  CAS  Google Scholar 

  • Delgado M, Sun W, Leceta J, Ganea D (1999a) 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 163:4213–4223

    PubMed  CAS  Google Scholar 

  • Delgado M, Leceta J, Gomariz RP, Ganea D (1999b) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide stimulate the induction of Th2 responses by up-regulating B7.2 expression. J Immunol 163:3629–3635

    PubMed  CAS  Google Scholar 

  • Delgado M, Munoz-Elias EJ, Gomariz RP, Ganea D (1999c) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide enhance IL-10 production by murine macrophages: in vitro and in vivo studies. J Immunol 162:1707–1716

    PubMed  CAS  Google Scholar 

  • Delgado M, Munoz-Elias EJ, Gomariz RP, Ganea D (1999d) VIP and PACAP inhibit IL-12 production in LPS-stimulated macrophages. Subsequent effect on IFNgamma synthesis by T cells. J Neuroimmunol 96:167–181

    Article  PubMed  CAS  Google Scholar 

  • Delgado M, Munoz-Elias EJ, Gomariz RP, Ganea D (1999e) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide prevent inducible nitric oxide synthase transcription in macrophages by inhibiting NF-kappa B and IFN regulatory factor 1 activation. J Immunol 162:4685–4696

    PubMed  CAS  Google Scholar 

  • Delgado M, Martinez C, Pozo D, Calvo JR, Leceta J, Ganea D, Gomariz RP (1999f) 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 162:1200–1205

    PubMed  CAS  Google Scholar 

  • Delgado M, Pozo D, Martinez C, Leceta J, Calvo JR, Ganea D, Gomariz RP (1999g) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit endotoxin-induced TNF-alpha production by macrophages: in vitro and in vivo studies. J Immunol 162:2358–2367

    PubMed  CAS  Google Scholar 

  • Delgado M, Leceta J, Sun W, Gomariz RP, Ganea D (2000a) VIP and PACAP induce shift to a Th2 response by upregulating B7.2 expression. Ann NY Acad Sci 921:68–78

    Article  PubMed  CAS  Google Scholar 

  • Delgado M, Gomariz RP, Martinez C, Abad C, Leceta J (2000b) Anti-inflammatory properties of the type 1 and type 2 vasoactive intestinal peptide receptors: role in lethal endotoxic shock. Eur J Immunol 30:3236–3246

    Article  PubMed  CAS  Google Scholar 

  • Delgado M, Abad C, Martinez C, Leceta J, Gomariz RP (2001) Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease. Nat Med 7:563–568

    Article  PubMed  CAS  Google Scholar 

  • Delgado M, Jonakait GM, Ganea D (2002a) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit chemokine production in activated microglia. Glia 39:148–161

    Article  PubMed  Google Scholar 

  • Delgado M, Leceta J, Ganea D (2002b) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide promote in vivo generation of memory Th2 cells. FASEB J 16:1844–1846

    PubMed  CAS  Google Scholar 

  • Delgado M, Leceta J, Ganea D (2003) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the production of inflammatory mediators by activated microglia. J Leukoc Biol 73:155–164

    Article  PubMed  CAS  Google Scholar 

  • Delgado M, Pozo D, Ganea D (2004a) The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev 56:249–290

    Article  PubMed  CAS  Google Scholar 

  • Delgado M, Gonzalez-Rey E, Ganea D (2004b) VIP/PACAP preferentially attract Th2 effectors through differential regulation of chemokine production by dendritic cells. FASEB J 18:1453–1455

    PubMed  CAS  Google Scholar 

  • Delgado M, Reduta A, Sharma V, Ganea D (2004c) VIP/PACAP oppositely affects immature and mature dendritic cell expression of CD80/CD86 and the stimulatory activity for CD4(+) T cells. J Leukoc Biol 75:1122–1130

    Article  PubMed  CAS  Google Scholar 

  • Delgado M, Gonzalez-Rey E, Ganea D (2005a) The neuropeptide vasoactive intestinal peptide generates tolerogenic dendritic cells. J Immunol 175:7311–7324

    PubMed  CAS  Google Scholar 

  • Delgado M, Chorny A, Gonzalez-Rey E, Ganea D (2005b) Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. J Leukoc Biol 78:1327–1338

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Martin A, Gonzalez-Rey E, Chorny A, Ganea D, Delgado M (2006) Vasoactive intestinal peptide induces regulatory T cells during experimental autoimmune encephalomyelitis. Eur J Immunol 36:318–326

    Article  PubMed  CAS  Google Scholar 

  • Foey AD, Field S, Ahmed S, Jain A, Feldmann M, Brennan FM, Williams R (2003) Impact of VIP and cAMP on the regulation of TNF-alpha and IL-10 production: implications for rheumatoid arthritis. Arthritis Res Ther 5:R317–328

    Article  PubMed  CAS  Google Scholar 

  • Ganea D, Delgado M (2003) The neuropeptides VIP/PACAP and T cells: inhibitors or activators? Curr Pharm Des 9:997–1004

    Article  PubMed  CAS  Google Scholar 

  • Ganea D, Rodriguez R, Delgado M (2003) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: players in innate and adaptive immunity. Cell Mol Biol (Noisy-le-grand) 49:127–142

    CAS  Google Scholar 

  • Goetzl EJ, Voice JK, Shen S, Dorsam G, Kong Y, West KM, Morrison CF, Harmar AJ (2001) 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 USA 98:13854–13859

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Rey E, Fernandez-Martin A, Chorny A, Delgado M (2006a) Vasoactive intestinal peptide induces CD4+, CD25+ T regulatory cells with therapeutic effect in collagen-induced arthritis. Arthritis Rheum 54:864–876

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Rey E, Fernandez-Martin A, Chorny A, Martin J, Pozo D, Ganea D, Delgado M (2006b) Therapeutic effect of vasoactive intestinal peptide on experimental autoimmune encephalomyelitis: down-regulation of inflammatory and autoimmune responses. Am J Pathol 168:1179–1188

    PubMed  CAS  Google Scholar 

  • Joffre O, van Meerwijk JP (2006) CD4(+)CD25(+) regulatory T lymphocytes in bone marrow transplantation. Semin Immunol 18:128–135

    Article  PubMed  CAS  Google Scholar 

  • Juarranz Y, Abad C, Martinez C, Arranz A, Gutierrez-Canas I, Rosignoli F, Gomariz RP, Leceta J (2005) Protective effect of vasoactive intestinal peptide on bone destruction in the collagen-induced arthritis model of rheumatoid arthritis. Arthritis Res Ther 7:R1034–1045

    Article  PubMed  CAS  Google Scholar 

  • Kaltreider HB, Ichikawa S, Byrd PK, Ingram DA, Kishiyama JL, Sreedharan SP, Warnock ML, Beck JM, Goetzl EJ (1997) Upregulation of neuropeptides and neuropeptide receptors in a murine model of immune inflammation in lung parenchyma. Am J Respir Cell Mol Biol 16:133–144

    PubMed  CAS  Google Scholar 

  • Kato H, Ito A, Kawanokuchi J, Jin S, Mizuno T, Ojika K, Ueda R, Suzumura A (2004) Pituitary adenylate cyclase-activating polypeptide (PACAP) ameliorates experimental autoimmune encephalomyelitis by suppressing the functions of antigen presenting cells. Mult Scler 10:651–659

    Article  PubMed  CAS  Google Scholar 

  • Keino H, Kezuka T, Takeuchi M, Yamakawa N, Hattori T, Usui M (2004) Prevention of experimental autoimmune uveoretinitis by vasoactive intestinal peptide. Arch Ophthalmol 122:1179–1184

    Article  PubMed  CAS  Google Scholar 

  • Kim WK, Kan Y, Ganea D, Hart RP, Gozes I, Jonakait GM (2000) Vasoactive intestinal peptide and pituitary adenylyl cyclase-activating polypeptide inhibit tumor necrosis factor-alpha production in injured spinal cord and in activated microglia via a cAMP-dependent pathway. J Neurosci 20:3622–3630

    PubMed  CAS  Google Scholar 

  • Kim WK, Ganea D, Jonakait GM (2002) Inhibition of microglial CD40 expression by pituitary adenylate cyclase-activating polypeptide is mediated by interleukin-10. J Neuroimmunol 126:16–24

    Article  PubMed  CAS  Google Scholar 

  • Lee CM, Kumar RK, Lubowski DZ, Burcher E (2002) Neuropeptides and nerve growth in inflammatory bowel diseases: a quantitative immunohistochemical study. Dig Dis Sci 47:495–502

    Article  PubMed  CAS  Google Scholar 

  • Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG (2005) Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood 105:1162–1169

    Article  PubMed  CAS  Google Scholar 

  • Martinez C, Delgado M, Pozo D, Leceta J, Calvo JR, Ganea D, Gomariz RP (1998) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide modulate endotoxin-induced IL-6 production by murine peritoneal macrophages. J Leukoc Biol 63:591–601

    PubMed  CAS  Google Scholar 

  • Martinez C, Juarranz Y, Abad C, Arranz A, Miguel BG, Rosignoli F, Leceta J, Gomariz RP (2005) Analysis of the role of the PAC1 receptor in neutrophil recruitment, acute-phase response, and nitric oxide production in septic shock. J Leukoc Biol 77:729–738

    Article  PubMed  CAS  Google Scholar 

  • Mosimann BL, White MV, Hohman RJ, Goldrich MS, Kaulbach HC, Kaliner MA (1993) Substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide increase in nasal secretions after allergen challenge in atopic patients. J Allergy Clin Immunol 92:95–104

    Article  PubMed  CAS  Google Scholar 

  • Nieber K, Baumgarten CR, Rathsack R, Furkert J, Oehme P, Kunkel G (1992) Substance P and beta-endorphin-like immunoreactivity in lavage fluids of subjects with and without allergic asthma. J Allergy Clin Immunol 90:646–652

    Article  PubMed  CAS  Google Scholar 

  • Owens T (2006) Animal models for multiple sclerosis. Adv Neurol 98:77–89

    PubMed  Google Scholar 

  • Rameshwar P, Gascon P, Oh HS, Denny TN, Zhu G, Ganea D (2002) Vasoactive intestinal peptide (VIP) inhibits the proliferation of bone marrow progenitors through the VPAC1 receptor. Exp Hematol 30:1001–1009

    Article  PubMed  CAS  Google Scholar 

  • Sharma V, Delgado M, Ganea D (2006) 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 176:97–110

    PubMed  CAS  Google Scholar 

  • Tuncel N, Tore F, Sahinturk V, Ak D, Tuncel M (2000) Vasoactive intestinal peptide inhibits degranulation and changes granular content of mast cells: a potential therapeutic strategy in controlling septic shock. Peptides 21:81–89

    Article  PubMed  CAS  Google Scholar 

  • Voice JK, Dorsam G, Lee H, Kong Y, Goetzl EJ (2001) Allergic diathesis in transgenic mice with constitutive T cell expression of inducible vasoactive intestinal peptide receptor. FASEB J 15:2489–2496

    Article  PubMed  CAS  Google Scholar 

  • Voice JK, Grinninger C, Kong Y, Bangale Y, Paul S, Goetzl EJ (2003) 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 170:308–314

    PubMed  CAS  Google Scholar 

  • Voice J, Donnelly S, Dorsam G, Dolganov G, Paul S, Goetzl EJ (2004) c-Maf and JunB mediation of Th2 differentiation induced by the type 2 G protein-coupled receptor (VPAC2) for vasoactive intestinal peptide. J Immunol 172:7289–7296

    PubMed  CAS  Google Scholar 

  • Xin Z, Sriram S (1998) Vasoactive intestinal peptide inhibits IL-12 and nitric oxide production in murine macrophages. J Neuroimmunol 89:206–212

    Article  PubMed  CAS  Google Scholar 

  • Zafirova Y, Yordanov M, Kalfin R (2004) Antiarthritic effect of VIP in relation to the host resistance against Candida albicans infection. Int Immunol 16:1125–1131

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was supported by NIH grant 2RO1 AI047325 (D.G. and M.D.), the Spanish Ministry of Health PI04/0674 (M.D.), and the Ramon Areces Foundation (M.D.).

Author information

Authors and Affiliations

  1. Department of Physiology, Temple University School of Medicine, 3420 N. Broad St., Philadelphia, PA, 19140, USA

    Doina Ganea

  2. Instituto de Parasitologia y Biomedicina, CSIC, Avd. Conocimiento, PT Ciencias de la Salud, Granada, 18100, Spain

    Elena Gonzalez-Rey & Mario Delgado

Authors
  1. Doina Ganea
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elena Gonzalez-Rey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mario Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Doina Ganea.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ganea, D., Gonzalez-Rey, E. & Delgado, M. A Novel Mechanism for Immunosuppression: from Neuropeptides to Regulatory T Cells. Jrnl Neuroimmune Pharm 1, 400–409 (2006). https://doi.org/10.1007/s11481-006-9044-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-006-9044-0

Key words

Search

Navigation