IL-17 stimulates inflammatory responses via NF-kappaB and MAP kinase pathways in human colonic myofibroblasts

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2002-06, Vol.282 (6), p.G1035-G1044
• Main Authors: Hata, Kazunori, Andoh, Akira, Shimada, Mitsue, Fujino, Sanae, Bamba, Shigeki, Araki, Yoshio, Okuno, Takafumi, Fujiyama, Yoshihide, Bamba, Tadao
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Cells, Cultured; Chemokine CCL2 - genetics; Chemokine CCL2 - secretion; Colon - cytology; Enzyme Inhibitors - pharmacology; Fibroblasts - drug effects; Fibroblasts - immunology; Fibroblasts - secretion; Gene Expression - drug effects; Gene Expression - immunology; Humans; Inflammatory Bowel Diseases - immunology; Interleukin-1 - pharmacology; Interleukin-17 - pharmacology; Interleukin-6 - genetics; Interleukin-6 - secretion; Interleukin-8 - genetics; Interleukin-8 - secretion; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Proline - analogs & derivatives; Proline - pharmacology; Protein Synthesis Inhibitors - pharmacology; RNA, Messenger - analysis; RNA, Messenger - metabolism; Thiocarbamates - pharmacology; Tosylphenylalanyl Chloromethyl Ketone - pharmacology; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0193-1857

Colonic subepithelial myofibroblasts (SEMFs) may play a role in the modulation of mucosal inflammatory responses. We investigated the effects of interleukin (IL)-17 on IL-6 and chemokine [IL-8 and monocyte chemoattractant protein (MCP)-1] secretion in colonic SEMFs. Cytokine expression was determined by ELISA and Northern blotting. Nuclear factor kappa B (NF-kappaB) DNA-binding activity was evaluated by electrophortetic gel mobility shift assay (EMSA). The activation of mitogen-activated protein kinase (MAPK) was assessed by immunoblotting. IL-6, IL-8, and MCP-1 secretions were rapidly induced by IL-17. IL-17 induced NF-kappaB activation within 45 min after stimulation. A blockade of NF-kappaB activation markedly reduced these responses. MAPK inhibitors (SB-203580, PD-98059, and U-0126) significantly reduced the IL-17-induced IL-6 and chemokine secretion. The combination of either IL-17 + IL-1beta or IL-17 + tumor necrosis factor (TNF)-alpha enhanced cytokine secretion; in particular, the effects of IL-17 + TNF-alpha on IL-6 secretion were much stronger than the other responses. This was dependent on the enhancement of IL-6 mRNA stability. In conclusion, human SEMFs secreted IL-6, IL-8, and MCP-1 in response to IL-17. These responses might play an important role in the pathogenesis of gut inflammation.