Neurokinin‐1 receptor (NK‐1R) expression is induced in human colonic epithelial cells by proinflammatory cytokines and mediates proliferation in response to substance P

Abstract

We have previously shown that the receptor for substance P (SP), neurokinin-1 receptor (NK-1R), is a marker of human mucosal but not peripheral mononuclear cells. In the present study, we investigate NK-1R expression in the human colonic mucosa in vivo, particularly in the epithelial cells. We investigate the influence of proinflammatory Th1 cytokines and SP on expression and function of NK-1R in colonic epithelial cells in vitro. Using in situ hybridization to detect NK-1R mRNA, and immunohistochemistry to detect NK-1R protein, colonic epithelial cells were found to express NK-1R in vivo. In contrast, colon epithelial cell lines (Caco-2, HT29, SW620, T84) were negative for NK-1R mRNA and protein. However, stimulation with a proinflammatory cytokine cocktail containing IFN-gamma, TNF-alpha, and IL-1beta, caused induction of NK-1R expression. Expression of NK-1R in human colonic epithelial cells in vivo may therefore reflect cytokine conditioning by the mucosal microenvironment. SP did not alter ion transport in monolayers of cytokine-treated T84 cells. While SP stimulated epithelial ion transport in colonic mucosae ex vivo, this was not a direct effect of SP on the epithelial cells, and appeared to be neurally mediated. However, SP (10(-10)-10(-8) M) elicited a dose-dependent proliferative effect on cytokine-stimulated, but not unstimulated, SW620 cells. Proliferation of the epithelial cells in response to SP was mediated specifically via cytokine-induced NK-1R, since an NK-1R-specific antagonist (Spantide 1) completely blocked SP-mediated proliferation in the cytokine-treated cells. Our results therefore demonstrate that proinflammatory cytokines induce expression of NK-1R in human colonic epithelial cell lines, and that SP induces proliferation of the epithelial cells via cytokine-induced NK-1R.

Substance P Promotes Diabetic Corneal Epithelial Wound Healing Through Molecular Mechanisms Mediated via the Neurokinin-1 Receptor

“…In the corneal epithelium 72 h after scrape, the local antagonist injection caused a significant delay of corneal epithelial wound healing (n = 5 per group) (C) as well as attenuated p-Akt and Ki-67 staining density in the regenerated corneal epithelium (D). *P < 0.05. corneal epithelial wound healing, whereas this regulation is impaired in diabetic corneal epithelium and rescued by SP via an autoregulatory mechanism (37,38). Moreover, SP restored the corneal sensitivity of diabetic mice close to the same level of normal mice, whereas local inhibition of SP-NK-1 receptor signaling caused decreased corneal sensitivity in normal mice similar to that in diabetic mice.…”

Rapid changes in substance P signaling and neutral endopeptidase induced by skin-scratching stimulation in mice

“…Thus, the expression of NK-1R was upregulated in response to skin-scratching stimulation. An in vitro study showed that proinflammatory cytokines such as IL-1b, TNF-a and/or IFN-g upregulated NK-1R expression [35]. Therefore, skinscratching stimulation may have upregulated these proinflammatory cytokines, thus leading to the enhancement of NK-1R expression.…”

Substance P mediates antiapoptotic responses in human colonocytes by Akt activation

“…Under normal conditions, NK-1R expression in colonocytes is low (36), but its expression is increased in colonocytes in IBD patients (36,37) and ileal epithelial cells during C. difficile toxin A-induced experimental enteritis (38). Previous studies also indicated expression of NK-1R in intestinal epithelial cells (4,5).…”