TY - JOUR T1 - Hemokinin-1 stimulates prostaglandin E2 production in human colon through activation of cyclooxygenase-2 and inhibition of 15-hydroxyprostaglandin dehydrogenase JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.186155 SP - jpet.111.186155 AU - Liying Dai AU - D Shevy Perera AU - Denis W King AU - Bridget R Southwell AU - Elizabeth Burcher AU - Lu Liu Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/09/28/jpet.111.186155.abstract N2 - 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 inflammatory bowel disease (IBD) patients, upregulation 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 (HK-1) and PGE2 production in normal human colon. Exogenous HK-1 (0.1 μM) for 4h 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 tachykinin receptor antagonists SR140333 (NK1) and SR48968 (NK2) and was also inhibited by COX-2 inhibitor NS-398 but not by COX-1 inhibitor 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 level. Notably, this was coupled with an 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. ER -