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 E 2 (PGE 2 ) occur. Our aim was to examine the mechanistic link between human HK-1 and PGE 2 production in normal human colon. Exogenous HK-1 (0.1 M) for 4 h evoked an increased PGE 2 release from colonic mucosal and muscle explants by 10-and 3.5-fold, respectively, compared with unstimulated time controls. The HK-1-stimulated PGE 2 release was inhibited by the tachykinin receptor antagonists (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 PGE 2 increase, in which HK-1 may interfere with the downstream metabolism of PGE 2 by suppressing 15-PGDH expression. In conclusion, our results uncover a novel inflammatory role for HK-1, which signals via NK 1 and NK 2 receptors to regulate PGE 2 release from human colonic tissue, and may further explain a pathological role for HK-1 in IBD when abnormal levels of PGE 2 occur.

Inflammation Modulation by Vitamin D and Calcium in the Morphologically Normal Colorectal Mucosa of Patients with Colorectal Adenoma in a Clinical Trial

“…A potential explanation for these findings is that combined calcium and vitamin D supplementation may act synergistically to lower PTH concentrations, thereby reducing 1,25(OH) 2 D synthesis in the kidneys and calcium absorption in the gut, compared with the use of either supplement alone (49). While tumor-associated stromal cells, including fibroblasts and macrophages, may play an important role in tumor development by secreting cytokines and regulating PG-mediated inflammation via COX-2 expression (50), consistent with a previous study (51), we found COX-2 and 15-HPGD expression to be generally lower in the stroma than in the crypt epithelium of the morphologically normal colorectal mucosa. This may be due, in part, to there being fewer cells in the stroma than in crypts, and could explain why our estimated calcium and/or vitamin D treatment effects were less pronounced there.…”

Gene expression of muscarinic, tachykinin, and purinergic receptors in porcine bladder: comparison with cultured cells

“…The gene sequence for NK 1 receptor in porcine genome is not published in NCBI, therefore, the primers for the NK 1 receptor were derived from sequences conserved across a broad range of mammalian species (human, cow, dog, and mouse). Gene expression was determined by quantitative real-time polymerase chain reaction (qRT-PCR) using the KAPA™ SYBR ® FAST kit as described (Liu et al, 2011; Dai et al, 2012). GAPDH was used as the housekeeping gene (HKG), and mRNA from an intact pig bladder tissue was used as the internal calibrator.…”

Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization

“…The discovery of the newest member of the tachykinin family, the hemokinin-1 (HK-1) encoded by the Tac4 gene [30], has given a new impetus to tachykinin research. HK-1 might be a novel key molecule in behavior, pain and inflammatory processes [31]. There is a growing amount of data regarding the mRNA expression of the Tac4 gene both in the central and peripheral nervous systems.…”