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A20 Inhibits Toll-Like Receptor 2– and 4–Mediated Interleukin-8 Synthesis in Airway Epithelial Cells

First Department of Internal Medicine, Nihon University School of Medicine, and Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Sciences, Tokyo, Japan

Address correspondence to: Shu Hashimoto, First Department of Internal Medicine, Nihon University School of Medicine, 30-1 Oyaguchikamimachi, Itabashi-ku, Tokyo 173–8610, Japan. E-mail: shuh{at}med.nihon-u.ac.jp

The zinc finger protein A20 is encoded by an immediate early response gene and acts as an inhibitor of nuclear factor (NF)-B–dependent gene expression induced by different stimuli, including tumor necrosis factor- (TNF-) and interleukin-1ß (IL-1ß). Toll-like receptor 2 (TLR2) and TLR4 have been found to transduce, respectively, peptidoglycan (PGN) and lipopolysaccharide (LPS) signals for the activation of NF-B and the production of inflammatory cytokines. Here, we have examined the role of A20 in TLR-mediated NF-B–dependent gene expression in human airway epithelial cells (AECs). Stimulation with LPS and PGN resulted in a significant increase in the level of A20 mRNA in primary cultured AECs and in NCI-H292 AECs. LPS and PGN induced activation of the IL-8 promoter both in NCI-H292 AECs and in HEK293 cells expressing either TLR2 or TLR4 plus MD-2. Dominant-negative myeloid differentiation protein and a mutant form of IB attenuated this PGN- or LPS-induced activation of the IL-8 promoter. Furthermore, overexpression of A20 inhibited activation of both NF-B and the IL-8 promoter by PGN or LPS in these cells. Taken together, our results suggest that A20 may function as a negative regulator of TLR-mediated inflammatory responses in the airway, thereby protecting the host against harmful overresponses to pathogens.

Abbreviations: airway epithelial cells, AECs • dominant-negative form, DN • fluorescence-activated cell sorter, FACS • interleukin, IL • IL-1 receptor –associated kinase-1, IRAK1 • lipopolysaccharide, LPS • myeloid differentiation protein, MyD88 • nuclear factor-B, NF-B • pathogen-associated molecular patterns, PAMPs • peptidoglycan, PGN • suppressor of cytokine-signaling-1, SOCS1 • Toll receptor–IL-1R domain–containing adapter protein, TIRAP • Toll-like receptor, TLR • tumor-necrosis factor-, TNF- • TNF receptor–associated factor, TRAF

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