title: Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M.
abstract: Glucocorticoids are among the most commonly used anti-inflammatory agents. Despite the enormous efforts in elucidating the glucocorticoid-mediated anti-inflammatory actions, how glucocorticoids tightly control overactive inflammatory response is not fully understood. Here we show that glucocorticoids suppress bacteria-induced inflammation by enhancing IRAK-M, a central negative regulator of Toll-like receptor signalling. The ability of glucocorticoids to suppress pulmonary inflammation induced by non-typeable Haemophilus influenzae is significantly attenuated in IRAK-M-deficient mice. Glucocorticoids improve the survival rate after a lethal non-typeable Haemophilus influenzae infection in wild-type mice, but not in IRAK-M-deficient mice. Moreover, we show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter. Together, our studies unveil a mechanism by which glucocorticoids tightly control the inflammatory response and host defense via the induction of IRAK-M and may lead to further development of anti-inflammatory therapeutic strategies.
authors.affiliation: Center for Inflammation, Immunity &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30302, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyata
authors.affiliation: Center for Inflammation, Immunity &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30302, USA.
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Center for Inflammation, Immunity &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30302, USA.
authors.forename: Seiko
authors.initials: S
authors.lastname: Susuki-Miyata
authors.affiliation: 1] Center for Inflammation, Immunity &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30302, USA [2] Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Wenzhuo Y
authors.initials: WY
authors.lastname: Wang
authors.affiliation: Center for Inflammation, Immunity &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30302, USA.
authors.forename: Haidong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
authors.affiliation: Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M Health Science Center, College Station, Texas 77843, USA.
authors.forename: Koichi S
authors.initials: KS
authors.lastname: Kobayashi
authors.affiliation: Department of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Center for Inflammation, Immunity &Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30302, USA.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D005938:Glucocorticoids / Q000627:therapeutic use*; D006193:Haemophilus influenzae / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D005938:Glucocorticoids; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse