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Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M

Author

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  • Masanori Miyata

    (Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University)

  • Ji-Yun Lee

    (Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University)

  • Seiko Susuki-Miyata

    (Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University)

  • Wenzhuo Y. Wang

    (Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University
    University of Rochester Medical Center)

  • Haidong Xu

    (Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University)

  • Hirofumi Kai

    (Graduate School of Pharmaceutical Sciences, Kumamoto University)

  • Koichi S. Kobayashi

    (College of Medicine, Texas A&M Health Science Center)

  • Richard A. Flavell

    (Yale University School of Medicine)

  • Jian-Dong Li

    (Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University)

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.

Suggested Citation

  • Masanori Miyata & Ji-Yun Lee & Seiko Susuki-Miyata & Wenzhuo Y. Wang & Haidong Xu & Hirofumi Kai & Koichi S. Kobayashi & Richard A. Flavell & Jian-Dong Li, 2015. "Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7062
    DOI: 10.1038/ncomms7062
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    Cited by:

    1. Trang H Nguyen & Ilona Turek & Terri Meehan-Andrews & Anita Zacharias & Helen R Irving, 2022. "A systematic review and meta-analyses of interleukin-1 receptor associated kinase 3 (IRAK3) action on inflammation in in vivo models for the study of sepsis," PLOS ONE, Public Library of Science, vol. 17(2), pages 1-24, February.

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