Human neutrophil peptides induce interleukin-8 in intestinal epithelial cells through the P2 receptor and ERK1/2 signaling pathways
| Autor: | Akio Ido, Kazunari Ibusuki, Hirofumi Uto, Masatsugu Numata, Takuro Maeda, Yuji Iwashita, Hirohito Tsubouchi, Yuichiro Nasu, Shuji Kanmura, Shinichi Hashimoto, Toshio Sakiyama, Hiroki Taguchi, Fumisato Sasaki |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Mitogen-Activated Protein Kinase 1
MAPK/ERK pathway alpha-Defensins Mitogen-Activated Protein Kinase 3 MAP Kinase Signaling System Receptors Purinergic P2 Interleukin-8 Thiourea General Medicine Biology chemistry.chemical_compound Intestinal mucosa chemistry Isothiocyanates Caco-2 Genetics Cancer research Humans PPADS Interleukin 8 Caco-2 Cells Intestinal Mucosa Signal transduction Receptor A431 cells |
| Zdroj: | International Journal of Molecular Medicine. 35:1603-1609 |
| ISSN: | 1791-244X 1107-3756 |
| DOI: | 10.3892/ijmm.2015.2156 |
| Popis: | 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, SB203580. 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. |
| Databáze: | OpenAIRE |
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