@phdthesis{oai:ir.kagoshima-u.ac.jp:00012057,
 author = {指宿, 和成 and Ibusuki, Kazunari},
 month = {2016-10-31, 2016-10-31},
 note = {博士論文全文, 博士論文要旨, Abstract. Human neutrophil peptides (HNPs) are antimicrobial peptides produced predominantly by neutrophils. We have previously reported that HNP 1-3 levels are increased in the sera and plasma of patients with active ulcerative colitis. The increased expression of interleukin-8 (IL-8) has also been demonstrated in the colonic mucosa of patients with active ulcerative colitis. HNPs induce IL-8 in lung epithelial cells and monocytes through the P2Y6 signaling pathway. However, the association between HNPs and IL-8 in the intestinal mucosa has not yet been investigated. In the present study, we investigated the effects of HNP-1 on the production of IL-8 by human intestinal epithelial cells and the underlying signaling mechanisms. We observed a significant increase in IL-8 expression in the human colon carcinoma cell line, Caco-2, following treatment with HNP-1. The non-selective P2 receptor antagonists, suramin and pyridoxal phosphate-6-azo (benzene-2,4-disulfonic acid) tetrasodium salt hydrate (PPADS), significantly blocked the HNP-1-induced expression of IL-8 in the Caco-2 cells. The P2Y6-specific antagonist, MRS2578, led to a significant but partial decrease in IL-8 expression, suggesting that P2 receptors in addition to P2Y6 are involved in the HNP-1-induced production of IL-8 by Caco-2 cells. In agreement with this finding, HNP-1 also significantly increased IL-8 production in the P2Y6-negative human colon cancer cell line, HT-29, and this increase was blocked by treatment with suramin and PPADS. HNP-1 significantly increased the phosphorylation of extracellular signal-regulated kinase 1/2(ERK1/2) and p38 mitogen-activated protein kinase (MAPK) in the HT-29 cells. However, the HNP-1-induced production of IL-8 was suppressed by the ERK1/2 inhibitor, U0126, but not by the p38 MAPK inhibitor, SB 203580. In conclusion, our data demonstrate that HNP-1 induces IL-8 production not only through P2Y6, but also through additional P2 receptors via an ERK1/2-dependent mechanism in intestinal epithelial cells.

Kazunari Ibusuki, Toshio Sakiyama, Shuji Kanmura, Takuro Maeda, Yuji Iwa shita, Yuichiro Nasu, Fumisato Sasaki, Hiroki Taguchi, Shinichi Hashimoto, Masat sugu Numata, Hirofumi Uto, Hirohito Tsubouchi and Akio Ido
Human neutrophil peptides induce interleukin-8 in intestinal epithelial cells through the P2 receptor and ERK1/2 signaling pathways
International Journal of Molecular Medicine, 2015, 35(6), p.1603-1609
https://doi.org/10.3892/ijmm.2015.2156},
 school = {鹿児島大学},
 title = {Human neutrophil peptides induce interleukin-8 in intestinal cells through the P2 receptor and ERK1/2 signaling pathways},
 year = {},
 yomi = {イブスキ, カズナリ}
}