title: TRPM8 activation attenuates inflammatory responses in mouse models of colitis.
abstract: Transient Receptor Potential Melastatin-8 (TRPM8), a recently identified member of the transient receptor potential (TRP) family of ion channels, is activated by mild cooling and by chemical compounds such as the supercooling agent, icilin. Since cooling, possibly involving TRPM8 stimulation, diminishes injury-induced peripheral inflammation, we hypothesized that TRPM8 activation may also attenuate systemic inflammation. We thus studied the involvement of TRPM8 in regulating colonic inflammation using two mouse models of chemically induced colitis. TRPM8 expression, localized immunohistochemically in transgenic TRPM8(GFP) mouse colon, was up-regulated in both human- and murine-inflamed colon samples, as measured by real-time PCR. Wild-type mice (but not TRPM8-nulls) treated systemically with the TRPM8 agonist, icilin showed an attenuation of chemically induced colitis, as reflected by a decrease in macroscopic and microscopic damage scores, bowel thickness, and myeloperoxidase activity compared with untreated animals. Furthermore, icilin treatment reduced the 2,4,6-trinitrobenzenesulfonic acid-induced increase in levels of inflammatory cytokines and chemokines in the colon. In comparison with wild-type mice, Dextran Sodium Sulfate (DSS)-treated TRPM8 knockout mice showed elevated colonic levels of the inflammatory neuropeptide calcitonin-gene-related peptide, although inflammatory indices were equivalent for both groups. Further, TRPM8 activation by icilin blocked capsaicin-triggered calcitonin-gene-related peptide release from colon tissue ex vivo and blocked capsaicin-triggered calcium signaling in Transient Receptor Potential Vaniloid-1 (TRPV1) and TRPM8 transfected HEK cells. Our data document an anti-inflammatory role for TRPM8 activation, in part due to an inhibiton of neuropeptide release, pointing to a novel therapeutic target for colitis and other inflammatory diseases.
authors.affiliation: Department of Physiology and Pharmacology, Inflammation Research Network, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada T2N 4N1. rramacha@ucalgary.ca
authors.forename: Rithwik
authors.initials: R
authors.lastname: Ramachandran
authors.forename: Eric
authors.initials: E
authors.lastname: Hyun
authors.forename: Liena
authors.initials: L
authors.lastname: Zhao
authors.forename: Tamia K
authors.initials: TK
authors.lastname: Lapointe
authors.forename: Kevin
authors.initials: K
authors.lastname: Chapman
authors.forename: Christina L
authors.initials: CL
authors.lastname: Hirota
authors.forename: Subrata
authors.initials: S
authors.lastname: Ghosh
authors.forename: David D
authors.initials: DD
authors.lastname: McKemy
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
authors.forename: Paul L
authors.initials: PL
authors.lastname: Beck
authors.forename: Christophe
authors.initials: C
authors.lastname: Altier
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D020013:Calcium Signaling; D018925:Chemokines / Q000378:metabolism; D003092:Colitis / Q000150:complications / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism; D015640:Ion Channel Gating; D051379:Mice; D018345:Mice, Knockout; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use; D050053:TRPM Cation Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D018925:Chemokines; D018836:Inflammation Mediators; D011744:Pyrimidinones; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; C492297:TRPM8 protein, mouse; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; C490483:icilin; D015740:Calcitonin Gene-Related Peptide