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TNF and IFN  Synergistically Enhance Transcriptional Activation of CXCL10 in Human Airway Smooth Muscle Cells via STAT-1, NF- B, and the Transcriptional Coactivator CREB-binding Protein

Clarke, D. L.; Clifford, R. L.; Jindarat, S.; Proud, D.; Pang, L.; Belvisi, M.; Knox, A. J.

Authors

D. L. Clarke

S. Jindarat

D. Proud

L. Pang

M. Belvisi

A. J. Knox



Abstract

Asthmatic airway smooth muscle (ASM) expresses interferon-?-inducible protein-10 (CXCL10), a chemokine known to mediate mast cell migration into ASM bundles that has been reported in the airways of asthmatic patients. CXCL10 is elevated in patients suffering from viral exacerbations of asthma and in patients with chronic obstructive pulmonary disease (COPD), diseases in which corticosteroids are largely ineffective. IFN? and TNF? synergistically induce CXCL10 release from human ASM cells in a steroid-insensitive manner, via an as yet undefined mechanism. We report that TNF? activates the classical NF-?B (nuclear factor ?B) pathway, whereas IFN? activates JAK2/STAT-1? and that inhibition of the JAK/STAT pathway is more effective in abrogating CXCL10 release than the steroid fluticasone. The synergy observed with TNF? and IFN? together, however, did not lie at the level of NF-?B activation, STAT-1? phosphorylation, or in vivo binding of these transcription factors to the CXCL10 promoter. Stimulation of human ASM cells with TNF? and IFN? induced histone H4 but not histone H3 acetylation at the CXCL10 promoter, although no synergism was observed when both cytokines were combined. We show, however, that TNF? and IFN? exert a synergistic effect on the recruitment of CREB-binding protein (CBP) to the CXCL10, which is accompanied by increased RNA polymerase II. Our results provide evidence that synergism between TNF? and IFN? lies at the level of coactivator recruitment in human ASM and suggest that inhibition of JAK/STAT signaling may be of therapeutic benefit in steroid-resistant airway disease.

Citation

Clarke, D. L., Clifford, R. L., Jindarat, S., Proud, D., Pang, L., Belvisi, M., & Knox, A. J. (2010). TNF and IFN  Synergistically Enhance Transcriptional Activation of CXCL10 in Human Airway Smooth Muscle Cells via STAT-1, NF- B, and the Transcriptional Coactivator CREB-binding Protein. Journal of Biological Chemistry, 285(38), 29101-29110. https://doi.org/10.1074/jbc.m109.0999952

Journal Article Type Article
Online Publication Date Sep 10, 2010
Publication Date Sep 17, 2010
Deposit Date Oct 16, 2019
Journal Journal of Biological Chemistry
Print ISSN 0021-9258
Electronic ISSN 1083-351X
Publisher American Society for Biochemistry and Molecular Biology
Peer Reviewed Peer Reviewed
Volume 285
Issue 38
Pages 29101-29110
DOI https://doi.org/10.1074/jbc.m109.0999952
Keywords Cell Biology; Biochemistry; Molecular Biology
Public URL https://nottingham-repository.worktribe.com/output/2847637
Publisher URL http://www.jbc.org/content/285/38/29101