title: Hemokinin-1 stimulates prostaglandin E₂ production in human colon through activation of cyclooxygenase-2 and inhibition of 15-hydroxyprostaglandin dehydrogenase.
abstract: Hemokinin-1 (HK-1) is a newly identified tachykinin, originating from the immune system rather than neurons, and may participate in the immune and inflammatory response. In colonic mucosa of patients with inflammatory bowel disease (IBD), up-regulation of the TAC4 gene encoding HK-1 and increased production of prostaglandin E₂ (PGE₂) occur. Our aim was to examine the mechanistic link between human HK-1 and PGE₂ production in normal human colon. Exogenous HK-1 (0.1 μM) for 4 h evoked an increased PGE₂ release from colonic mucosal and muscle explants by 10- and 3.5-fold, respectively, compared with unstimulated time controls. The HK-1-stimulated PGE₂ release was inhibited by the tachykinin receptor antagonists (S)1-2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl-4-phenyl-l azonia-bicyclo[2.2.2]octane (SR140333) [neurokinin-1 (NK₁)] and N-[(2S)-4-(4-acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide (SR48968) [neurokinin-2 (NK₂)] and was also inhibited by the cyclooxygenase (COX)-2 inhibitor N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide) (NS-398) but not by the COX-1 inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560). A parallel study with substance P showed similar results. Molecular studies with HK-1-treated explants demonstrated a stimulatory effect on COX-2 expression at both transcription and protein levels. It is noteworthy that this was coupled with HK-1-induced down-regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) mRNA and protein expression. Immunoreactivity for 15-PGDH occurred on inflammatory cells, epithelial cells, platelets, and ganglia. This finding provides an additional mechanism for HK-1-evoked PGE₂ increase, in which HK-1 may interfere with the downstream metabolism of PGE₂ by suppressing 15-PGDH expression. In conclusion, our results uncover a novel inflammatory role for HK-1, which signals via NK₁ and NK₂ receptors to regulate PGE₂ release from human colonic tissue, and may further explain a pathological role for HK-1 in IBD when abnormal levels of PGE₂ occur.
authors.affiliation: Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, Australia.
authors.forename: Liying
authors.initials: L
authors.lastname: Dai
authors.forename: D Shevy
authors.initials: DS
authors.lastname: Perera
authors.forename: Denis W
authors.initials: DW
authors.lastname: King
authors.forename: Bridget R
authors.initials: BR
authors.lastname: Southwell
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Burcher
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D003092:Colitis / Q000503:physiopathology; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical; D015320:Tachykinins / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; C507968:hemokinin-1; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2; D015232:Dinoprostone