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International Immunology Advance Access originally published online on May 19, 2008
International Immunology 2008 20(7):901-909; doi:10.1093/intimm/dxn048
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

The NF-{kappa}B, p38 MAPK and STAT1 pathways differentially regulate the dsRNA-mediated innate immune responses of epidermal keratinocytes

Xiuju Dai, Koji Sayama, Mikiko Tohyama, Yuji Shirakata, Lujun Yang, Satoshi Hirakawa, Sho Tokumaru and Koji Hashimoto

Department of Dermatology, Ehime University Graduate School of Medicine, Toon-city, Ehime 791-0295, Japan

Correspondence to: K. Sayama; E-mail: sayama{at}m.ehime-u.ac.jp

The epidermis is the primary boundary between the body and the environment, and it serves as the first line of defense against microbial pathogens. Production of chemokines and cytokines is an important step in the initiation of innate immune responses to viral infections. Epidermal keratinocytes produce IFN-{alpha}, -β and macrophage inflammatory protein (MIP)-1{alpha} in response to double-stranded RNA (dsRNA) or viral infections. We showed that human keratinocytes produced cytokines [tumor necrosis factor (TNF)-{alpha}, IL-1β and IL-15] and chemokines [MIP-1β, RANTES and liver and activation-regulated chemokine (LARC)] in response to dsRNA, with activation of the nuclear factor {kappa}B (NF-{kappa}B), p38 mitogen-activated protein kinase (MAPK) and signal transducers and activators of transcription 1 (STAT1) pathways. To study the roles of these pathways in their production, we transfected keratinocytes with adenoviral vectors (Ax) carrying a dominant-negative form of inhibitor {kappa}B {alpha} (I{kappa}B{alpha}) (I{kappa}B{alpha}M), a dominant-negative mutant form of STAT1 (STAT1F) or suppressors of cytokine signaling 1 (SOCS1). Transfection with AxI{kappa}B{alpha}M or addition of a p38 inhibitor (SB203580) significantly decreased the dsRNA-mediated production of TNF-{alpha}, IL-1β and MIP-1{alpha}, but not of IFN-β, IL-15, MIP-1β, RANTES or LARC. Transfection with AxSTAT1F or AxSOCS1 inhibited the dsRNA-mediated production of TNF-{alpha}, IL-15, MIP-1{alpha}, MIP-1β, RANTES and LARC, but not IFN-β or IL-1β. In conclusion, the NF-{kappa}B, p38 MAPK and STAT1 pathways differentially regulate dsRNA-mediated innate immune responses in epidermal keratinocytes.

Keywords: chemokines, cytokine, innate immunity, IRF3, SOCS1

Transmitting editor: E. Vivier

Received 19 December 2007, accepted 22 April 2008.


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