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

• Published in: Journal of cellular physiology 2003-10, Vol.197 (1), p.30-41
• Main Authors: Goode, Triona, O'Connor, Terry, Hopkins, Ann, Moriarty, Derek, O'Sullivan, Gearld C., Collins, J. Kevin, O'Donoghue, Diarmuid, Baird, Alan W., O'Connell, Joe, Shanahan, Fergus
• Format: Article
• Language: English
• Subjects: Caco-2 Cells; Cell Division - drug effects; Cell Division - physiology; Colon - cytology; Cytokines - metabolism; Dose-Response Relationship, Drug; Epithelial Cells - cytology; Epithelial Cells - metabolism; Gene Expression Regulation; HT29 Cells; Humans; Immunohistochemistry; In Situ Hybridization; Intestinal Mucosa - metabolism; Ion Transport - drug effects; Receptors, Neurokinin-1 - biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; Substance P - metabolism
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.10234

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‐γ, TNF‐α, and IL‐1β, 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. J. Cell. Physiol. 197: 30–41, 2003© 2003 Wiley‐Liss, Inc.