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TNFα and IFNγ Synergistically Enhance Transcriptional Activation of CXCL10 in Human Airway Smooth Muscle Cells via STAT-1, NF-κB, and the Transcriptional Coactivator CREB-binding Protein
被引:117
作者:
Clarke, Deborah L.
[3
]
Clifford, Rachel L.
[1
]
Jindarat, Sarawut
[1
]
Proud, David
[2
]
Pang, Linhua
[1
]
Belvisi, Maria
[3
]
Knox, Alan J.
[1
]
机构:
[1] Univ Nottingham, City Hosp, Nottingham Resp Biomed Res Unit, Nottingham NG5 1PB, England
[2] Univ Calgary, Dept Physiol & Biophys, Calgary, AB T2N 4N1, Canada
[3] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW7 2AZ, England
基金:
英国生物技术与生命科学研究理事会;
关键词:
NECROSIS-FACTOR-ALPHA;
HISTONE H4 ACETYLATION;
OBSTRUCTIVE PULMONARY-DISEASE;
BRONCHIAL EPITHELIAL-CELLS;
RNA-POLYMERASE-II;
INTERFERON-GAMMA;
GENE-TRANSCRIPTION;
GLUCOCORTICOID-RECEPTOR;
DEPENDENT TRANSCRIPTION;
INDUCIBLE PROTEIN-10;
D O I:
10.1074/jbc.M109.0999952
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Asthmatic airway smooth muscle (ASM) expresses interferon-gamma-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 gamma and TNF alpha synergistically induce CXCL10 release from human ASM cells in a steroid-insensitive manner, via an as yet undefined mechanism. We report that TNF alpha activates the classical NF-kappa B (nuclear factor kappa B) pathway, whereas IFN gamma activates JAK2/STAT-1 alpha and that inhibition of the JAK/STAT pathway is more effective in abrogating CXCL10 release than the steroid fluticasone. The synergy observed with TNF alpha and IFN gamma together, however, did not lie at the level of NF-kappa B activation, STAT-1 alpha phosphorylation, or in vivo binding of these transcription factors to the CXCL10 promoter. Stimulation of human ASM cells with TNF alpha and IFN gamma 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 alpha and IFN gamma 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 alpha and IFN gamma 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.
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页码:29101 / 29110
页数:10
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