Mechanisms of asthma and allergic inflammation: The IL-17F signaling pathway is involved in the induction of IFN- gamma -inducible protein 10 in bronchial epithelial cells

• Published in: Journal of allergy and clinical immunology 2007-06, Vol.119 (6), p.1408-1414
• Main Authors: Kawaguchi, Mio, Kokubu, Fumio, Huang, Shau-Ku, Homma, Tetsuya, Odaka, Miho, Watanabe, Shin, Suzuki, Shintaro, Ieki, Koushi, Matsukura, Satoshi, Kurokawa, Masatsugu, Adachi, Mitsuru
• Format: Article
• Language: English
• ISSN: 0091-6749
• DOI: 10.1016/j.jaci.2007.02.036

Background: IL-17F is involved in airway inflammation, but its biologic activity and signaling pathway remain incompletely defined. Interferon-?inducible protein 10 (IP-10) is widely expressed and plays a role in airway inflammatory diseases. Objective: We sought to investigate the functional linkage between IL-17F and IP-10 expression in bronchial epithelial cells. Methods: Bronchial epithelial cells were cultured in the presence or absence of IL-17F, and/or a TH1 cytokine, TH2 cytokines, proinflammatory cytokines, various kinase inhibitors, or a Raf1 dominant-negative mutant to analyze the expression of IP-10. Moreover, the involvement of p90 ribosomal S6 kinase (p90RSK) and cyclic AMP response elementbinding protein (CREB) in IL-17Finduced IP-10 expression were investigated. Results: IL-17F induces the gene and protein expression of IP-10. The addition of IFN-?, IL-1?, and TNF-? augmented IL-17Finduced IP-10 expression. The mitogen-activated protein kinase kinase (MEK) inhibitors PD98059, U0126, and Raf1 kinase inhibitor I significantly inhibited its production. In contrast, a p38 inhibitor, a JNK inhibitor, protein kinase C inhibitors, and a phosphatidylinositol 3-kinase inhibitor, showed no inhibitory effect. Furthermore, overexpression of a Raf1 dominant-negative mutant inhibited its expression. Of interest, IL-17F phosphorylated p90RSK and CREB, and transfection of the cells with a short interfering RNA for p90RSK or CREB inhibited its expression, suggesting p90RSK and CREB as novel signaling molecules of IL-17F. Conclusion: IL-17F is a potent inducer of IP-10 in bronchial epithelial cells through the activation of the Raf1MEK1/2extracellular signalregulated kinase 1/2p90RSKCREB pathway, supporting its regulatory role in airway inflammation. Clinical implications: The IL-17FIP-10 axis might be a novel and critical therapeutic target for airway inflammatory diseases.