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Glucocorticoid suppression of CX 3 CL1 (fractalkine) by reduced gene promoter recruitment of NF‐κB
Author(s) -
Bhavsar Pankaj K.,
Sukkar Maria B.,
Khorasani Nadia,
Lee KangYun,
Fan Chung Kian
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-094235
Subject(s) - glucocorticoid receptor , chromatin immunoprecipitation , microbiology and biotechnology , tumor necrosis factor alpha , glucocorticoid , promoter , biology , gene expression , chemistry , cancer research , endocrinology , gene , biochemistry
Glucocorticoids are an important antiinflammatory treatment of many inflammatory diseases including asthma. However, the mechanisms by which they mediate their suppressive effects are not fully understood. Respiratory epithelial cells are a source of CX 3 CL1 (fractalkine), which mediates cell adhesion and acts as a chemoattractant for monocytes, T cells, and mast cells. We show, in lung A549 epithelial cells, that the tumor necrosis factor‐α (TNF‐α) and IFNγ synergistically induced protein release and mRNA expression of CX 3 CL1 is inhibited by dexamethasone, without interfering with cytokine‐induced nuclear translocation of NF‐κB, and by an inhibitor of IκB kinase 2, AS602868. DNA binding assays confirmed the ability of NF‐κB to bind to the proximal CX 3 CL1 promoter. Chromatin immunoprecipitation assays showed a 5‐fold increase in the recruitment of NF‐κB to the CX 3 CL1 gene promoter in response to IFNγ/TNF‐α; this too was reversed by dexamethasone. In contrast, dexameth‐asone did not displace NF‐κB from the granulocyte‐macrophage colony‐stimulating factor gene promoter. We conclude that CX 3 CL1 expression is regulated through the NF‐κB pathway and that dexamethasone inhibits CX 3 CL1 expression through a glucocorticoid receptor‐dependent (RU486 sensitive) mechanism. This study also provides support for the action of glucocorticoids mediating their suppressive effects on expression by interfering with the binding of transcriptional activators at native gene promoters.— Bhavsar P. K., Sukkar, M. B., Khorasani, N., Lee, K.‐Y., Chung K. F. Glucocorticoid suppression of CX3CL1 (frac‐talkine) by reduced gene promoter recruitment of NF‐kB. FASEB J. 22, 1807–1816 (2008)