Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor

Blood. 2007 Apr 15;109(8):3139-46. doi: 10.1182/blood-2006-10-052787. Epub 2006 Dec 7.

Abstract

Although typically considered a neurotransmitter, there is substantial evidence that serotonin (5-HT) plays an important role in the pathogenesis of inflammatory disorders. Despite these findings, the precise role of 5-HT in modulating immune function, particularly T-cell function, remains elusive. We report that naive T cells predominantly express the type 7 5-HT receptor (5-HTR), and expression of this protein is substantially enhanced on T-cell activation. In addition, T-cell activation leads to expression of the 5-HT(1B) and 5-HT(2A) receptors. Significantly, exogenous 5-HT induces rapid phosphorylation of extracellular signal-regulated kinase-1 and -2 (ERK1/2) and IkappaBalpha in naive T cells. 5-HT-induced activation of ERK1/2 and NFkappaB is inhibited by preincubation with a specific 5-HT(7) receptor antagonist. Thus, 5-HT signaling via the 5-HT(7) receptor may contribute to early T-cell activation. In turn, 5-HT synthesized by T cells may act as an autocrine factor. Consistent with this hypothesis, we found that inhibition of 5-HT synthesis with parachlorophenylalanine (PCPA) impairs T-cell activation and proliferation. Combined, these data demonstrate a fundamental role for 5-HT as an intrinsic cofactor in T-cell activation and function and suggest an alternative mechanism through which immune function may be regulated by indoleamine 2,3-dioxygenase-mediated catabolism of tryptophan.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication / drug effects
  • Autocrine Communication / immunology*
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Fenclonine / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • I-kappa B Proteins / immunology
  • I-kappa B Proteins / metabolism
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Inflammation / immunology
  • Inflammation / metabolism
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinase 1 / immunology
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / immunology
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • NF-KappaB Inhibitor alpha
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein Processing, Post-Translational / immunology
  • Receptor, Serotonin, 5-HT1B / biosynthesis
  • Receptor, Serotonin, 5-HT1B / immunology
  • Receptors, Serotonin / immunology*
  • Receptors, Serotonin / metabolism
  • Serotonin / immunology*
  • Serotonin / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • I-kappa B Proteins
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Nfkbia protein, mouse
  • Receptor, Serotonin, 5-HT1B
  • Receptors, Serotonin
  • serotonin 7 receptor
  • NF-KappaB Inhibitor alpha
  • Serotonin
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Fenclonine