Glucocorticoid suppression of CX3CL1 (fractalkine) by reduced gene promoter recruitment of NF-κB

Pankaj K. Bhavsar, Maria B. Sukkar, Nadia Khorasani, Kang Yun Lee, Kian Fan Chung

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Glucocorticoids are an important anti-inflammatory 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 CX3CL1 (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 CX3CL1 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 CX3CL1 promoter. Chromatin immunoprecipitation assays showed a 5-fold increase in the recruitment of NF-κB to the CX3CL1 gene promoter in response to IFNγ/TNF-α; this too was reversed by dexamethasone. In contrast, dexamethasone did not displace NF-κB from the granulocyte-macrophage colony-stimulating factor gene promoter. We conclude that CX3CL1 expression is regulated through the NF-κB pathway and that dexamethasone inhibits CX3CL1 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.

Original languageEnglish
Pages (from-to)1807-1816
Number of pages10
JournalFASEB Journal
Volume22
Issue number6
DOIs
Publication statusPublished - Jun 2008
Externally publishedYes

Keywords

  • Chromatin
  • Displacement
  • Epithelial cells
  • Transcription factor

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology
  • Medicine(all)

Fingerprint Dive into the research topics of 'Glucocorticoid suppression of CX3CL1 (fractalkine) by reduced gene promoter recruitment of NF-κB'. Together they form a unique fingerprint.

  • Cite this