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Corticosteroid and Cytokines Synergistically Enhance Toll-Like Receptor 2 Expression in Respiratory Epithelial Cells

Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo; Division of Allergy, National Center for Child Health and Development, Tokyo; Department of Otorhinolaryngology, Jikei Medical School, Tokyo; Departments of Microbiology and Pediatrics, Kochi Medical School, Kochi; Research Team for Allergy Transcriptome, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

Address correspondence to: Kenji Matsumoto, M.D., Ph.D., Department of Allergy and Immunology, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya-ku, Tokyo 154-8567, Japan. E-mail: kmatsumoto{at}nch.go.jp

Respiratory epithelial cells play important roles not only in host defense mechanisms, but also in inflammatory responses. Inhaled corticosteroids are widely used for the treatment of patients with inflammatory lung disorders, including asthma, chronic obstructive pulmonary disease, and sarcoidosis. Corticosteroids effectively reduce the production of inflammatory mediators, such as cytokines and chemokines. Although these molecules are also essential for host defense responses, there is no convincing evidence that inhaled corticosteroids increase susceptibility to lower respiratory tract infections. To test the involvement of Toll-like receptor (TLR) family molecules in this phenomenon, we examined the effects of various cytokines and corticosteroid on the expression of TLRs in human respiratory epithelial cells. Among the TLRs tested, TLR2 expression was significantly enhanced after stimulation with a combination of tumor necrosis factor– and interferon-. Dexamethasone synergistically enhanced TLR2 expression in combination with tumor necrosis factor– and interferon- in terms of both mRNA and protein levels. Furthermore, increased cell-surface TLR2 was functional, judging from the remarkable induction of interleukin-6, interleukin-8, and ß-defensin–2 after stimulation with peptidoglycan. These results provide evidence for a novel function of corticosteroids in airway inflammatory disorders, and indicate that the use of inhaled corticosteroids in such disorders may have a beneficial role in host defense mechanisms.

Abbreviations: bacterial lipoprotein, BLP • dexamethasone, DEX • fluorescence-activated cell sorter, FACS • glucocorticoid receptor, GR • glucocorticoid response element, GRE • human ß-defensin–2, hBD2 • interferon, IFN • interleukin, IL • lipopolysaccharide, LPS • mitogen-activated protein kinase, MAPK • mean fluorescence intensity, MFI • MAPK phosphatase-1, MKP-1 • nuclear factor, NF • normal human bronchial epithelial cells, NHBE • nontypeable Haemophilus influenzae, NTHi • pathogen-associated molecular patterns, PAMPs • peripheral blood mononuclear cells, PBMC • peptidoglycan, PGN • Toll-like receptor, TLR • tumor necrosis factor, TNF • reverse transcriptase–polymerase chain reaction, RT-PCR

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