Opposite effects of substance P and calcitonin gene-related peptide in oxazolone colitis

Abstract

Background: Extrinsic sensory neurons play a crucial role in aberrant immune responses in colitis. The activation of peptidergic sensory nerve fibres is accompanied by a release of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). SP levels increase whilst CGRP levels decrease in colon specimens from patients with inflammatory bowel disease; thus suggesting the pro- and anti-inflammatory roles, respectively, of these neuropeptides.

Methods: Oxazolone (4-ethoxymethylene-2-phenyl-2-oxazolin-5-one) colitis was induced in wild-type (WT), SP and CGRP knockout ((-/-)) mice. CGRP(-/-) mice were treated with the neurokinin 1-receptor antagonist CP-96345 (CP). The permeability of the mouse colon was evaluated by Evans Blue uptake. Cytokines produced by colonic lamina propria mononuclear cells were measured by ELISA.

Results: Colons of WT, CGRP(-/-) and SP(-/-) mice showed similar tissue architecture and permeability. SP(-/-) mice were protected against oxazolone colitis, whereas CGRP(-/-) showed increased susceptibility to colitis compared to WT mice. SP(-/-) and CP-treated CGRP(-/-) mice showed no significant body weight loss during the period of sickness in contrast to untreated CGRP(-/-) and WT mice. Decreased production of IL-4, IL-5, and IL-13 by colonic lamina propria mononuclear cells of the protected SP(-/-) mice confirms the crucial role of these cytokines in oxazolone colitis.

Conclusion: We demonstrate that the neuropeptides CGRP and SP exert opposing effects in oxazolone colitis and provide further evidence for a prominent neuroimmune association in the gut.