Corticosteroid and cytokines synergistically enhance toll-like receptor 2 expression in respiratory epithelial cells.
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-alpha and interferon-gamma. Dexamethasone synergistically enhanced TLR2 expression in combination with tumor necrosis factor-alpha and interferon-gamma 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 beta-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.
Homma
Toshiki
T
Department of Allergy and Immunology, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya-ku, Tokyo 154-8567, Japan.
Kato
Atsushi
A
Hashimoto
Noriko
N
Batchelor
Jonathan
J
Yoshikawa
Mamoru
M
Imai
Shosuke
S
Wakiguchi
Hiroshi
H
Saito
Hirohisa
H
Matsumoto
Kenji
K
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D003907:Dexamethasone / Q000008:administration & dosage; D004357:Drug Synergism; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010457:Peptidoglycan / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage; D023083:beta-Defensins / Q000378:metabolism
C106641:DEFB4A protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D010457:Peptidoglycan; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; D003907:Dexamethasone; D007371:Interferon-gamma