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

Asthmatic airway smooth muscle (ASM) expresses interferon-γ-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. IFNγ and TNFα synergistically induce CXCL10 release from human ASM cells in a steroid-insensitive manner, via an as yet undefined mechanism. We report that TNFα activates the classical NF-κB (nuclear factor κB) pathway, whereas IFNγ activates JAK2/STAT-1α and that inhibition of the JAK/STAT pathway is more effective in abrogating CXCL10 release than the steroid fluticasone. The synergy observed with TNFα and IFNγ together, however, did not lie at the level of NF-κB activation, STAT-1α phosphorylation, or in vivo binding of these transcription factors to the CXCL10 promoter. Stimulation of human ASM cells with TNFα and IFNγ 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 TNFα and IFNγ 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 TNFα and IFNγ 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. Asthmatic airway smooth muscle (ASM) expresses interferon-γ-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. IFNγ and TNFα synergistically induce CXCL10 release from human ASM cells in a steroid-insensitive manner, via an as yet undefined mechanism. We report that TNFα activates the classical NF-κB (nuclear factor κB) pathway, whereas IFNγ activates JAK2/STAT-1α and that inhibition of the JAK/STAT pathway is more effective in abrogating CXCL10 release than the steroid fluticasone. The synergy observed with TNFα and IFNγ together, however, did not lie at the level of NF-κB activation, STAT-1α phosphorylation, or in vivo binding of these transcription factors to the CXCL10 promoter. Stimulation of human ASM cells with TNFα and IFNγ 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 TNFα and IFNγ 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 TNFα and IFNγ 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. IntroductionLung diseases such as asthma and COPD 2The abbreviations used are: COPDchronic obstructive pulmonary diseaseHASMhuman airway smooth muscleCBPCREB binding proteinCREBcAMP-response element-binding proteinISREIFN-stimulated responsive elementAPactivator protein. cause significant morbidity and mortality in Western societies. 5–10% of the asthmatic population are unresponsive to corticosteroids, the mainstay for asthma therapy, and patients with COPD are treated ineffectively with steroids. Additionally, viral exacerbations of asthma are a major cause of morbidity and mortality associated with asthma and are relatively unresponsive to steroids (1Johnston N.W. Johnston S.L. Duncan J.M. Greene J.M. Kebadze T. Keith P.K. Roy M. Waserman S. Sears M.R. J. Allergy Clin. Immunol. 2005; 115: 132-138Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 2Pauwels R.A. Pedersen S. Busse W.W. Tan W.C. Chen Y.Z. Ohlsson S.V. Ullman A. Lamm C.J. O'Byrne P.M. Lancet. 2003; 361: 1071-1076Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar).CXCL10, a member of the CXC chemokine subfamily, is a potent chemoattractant for mast cells and T lymphocytes, cells implicated in the pathophysiology of asthma and COPD. CXCL10 is elevated in the airways of asthmatic patients and has been implicated in mast cell migration to the ASM bundles (3Bradding P. Brightling Full Text Full Text PDF PubMed Scopus Google CXCL10 is elevated in the and of with which is largely steroid-resistant S. J. S. C.J. J. Immunol. PubMed Scopus Google CXCL10 has been in COPD S. J. J. PubMed Scopus Google Scholar, M. R.A. J. PubMed Scopus Google Scholar, M. M. P. S. A. J. PubMed Scopus Google and more has been reported that CXCL10 are increased to a in with asthma with and increased are of asthma exacerbations Johnston S.L. J. J. A. J. Allergy Clin. Immunol. Full Text Full Text PDF PubMed Scopus Google CXCL10 is in to IFNγ or TNFα from a of cell M. R.A. J. 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Immunol. 2005; PubMed Scopus Google Scholar, A. J. Immunol. PubMed Scopus Google We that TNFα and IFNγ synergistically the coactivator to the CXCL10 with recruitment of RNA polymerase to the promoter, that was the cause of synergistic effect on CXCL10 to the effect of transcription factor in steroid of airway the CXCL10 in steroid-resistant airway asthma exacerbations and COPD (3Bradding P. Brightling Full Text Full Text PDF PubMed Scopus Google Scholar, Johnston S.L. J. J. A. J. Allergy Clin. Immunol. Full Text Full Text PDF PubMed Scopus Google We that CXCL10 release was by both the steroid and the A. M. T. PubMed Scopus Google in to M. R.A. J. PubMed Scopus Google IFNγ induced NF-κB activation, was the release of CXCL10 induced by IFNγ by that release was to the of transcription factor in these in the that IFNγ is to CXCL10 release in human cells in an manner, yet of NF-κB J. Immunol. 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PubMed Scopus Google TNFα and IFNγ were to synergistically CXCL10 release via the recruitment of or STAT-1α to the CXCL10 and these cytokines in histone H3 H4 IFNγ has been reported to with TNFα to of R.A. S. PubMed Scopus Google and CXCL10, and M. R.A. J. PubMed Scopus Google Scholar, M. A. J. Immunol. Google Scholar, S. J. PubMed Scopus Google that used a of IFNγ and TNFα that the synergistic may be by the of TNFα Full Text PDF PubMed Scopus Google or T. J. Immunol. Google both cytokines may at the level by a synergistic between transcription factors by IFNγ and TNFα J. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google the the used were to synergistically CXCL10 release but no effect on the of transcription factor not such be the of as as by TNFα via of the of S. P. R.A. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, R.A. S. PubMed Scopus Google no synergistic recruitment of or histone H4 when TNFα and IFNγ were used in did a synergistic recruitment of the coactivator and RNA polymerase to the CXCL10 promoter, CXCL10 to the steroid observed these is not known or not of CXCL10 by transcription factors or recruitment to the CXCL10 steroid is to the of steroid and M. R.A. J. PubMed Scopus Google report a synergistic of CXCL10 of cells with TNFα and has been reported that IFNγ NF-κB and release S. PubMed Scopus Google The are but may the recruitment of transcription factors in to on such as in as yet is the in cells the synergistic of a coactivator and RNA polymerase by and J. Immunol. PubMed Scopus Google reported that in RNA polymerase with and to the promoter, in to histone H4 and H3 and M. 2005; PubMed Scopus Google reported that recruitment of RNA polymerase to the Additionally, and M. J. 2003; Full Text Full Text PDF PubMed Scopus Google report to in that the synergy observed TNFα and IFNγ on release in and human cells from the recruitment of RNA polymerase to the via of with and steroid is observed in 5–10% of the asthmatic to morbidity and and these for of the for asthma Full Text Full Text PDF PubMed Scopus Google Additionally, steroids are relatively in exacerbations of asthma induced by (1Johnston N.W. Johnston S.L. Duncan J.M. Greene J.M. Kebadze T. Keith P.K. Roy M. Waserman S. Sears M.R. J. Allergy Clin. Immunol. 2005; 115: 132-138Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 2Pauwels R.A. Pedersen S. Busse W.W. Tan W.C. Chen Y.Z. Ohlsson S.V. Ullman A. Lamm C.J. O'Byrne P.M. Lancet. 2003; 361: 1071-1076Abstract Full Text Full Text PDF PubMed Scopus (662) Google CXCL10 is increased Johnston S.L. J. J. A. J. Allergy Clin. Immunol. Full Text Full Text PDF PubMed Scopus Google therapeutic are to of has been reported to be an effective in a and of S. P. PubMed Scopus Google and A. S. 2005; PubMed Scopus Google inhibition of has to be an effective in a of pulmonary M. P. J. PubMed Scopus Google these are and be for Our suggest that of and signaling is more effective than the steroid in an in of steroid-resistant and may provide a of in diseases such as asthma and COPD that are to such IntroductionLung diseases such as asthma and COPD 2The abbreviations used are: COPDchronic obstructive pulmonary diseaseHASMhuman airway smooth muscleCBPCREB binding proteinCREBcAMP-response element-binding proteinISREIFN-stimulated responsive elementAPactivator protein. cause significant morbidity and mortality in Western societies. 5–10% of the asthmatic population are unresponsive to corticosteroids, the mainstay for asthma therapy, and patients with COPD are treated ineffectively with steroids. Additionally, viral exacerbations of asthma are a major cause of morbidity and mortality associated with asthma and are relatively unresponsive to steroids (1Johnston N.W. Johnston S.L. Duncan J.M. Greene J.M. Kebadze T. Keith P.K. Roy M. Waserman S. Sears M.R. J. Allergy Clin. Immunol. 2005; 115: 132-138Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 2Pauwels R.A. Pedersen S. Busse W.W. Tan W.C. Chen Y.Z. Ohlsson S.V. Ullman A. Lamm C.J. O'Byrne P.M. Lancet. 2003; 361: 1071-1076Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar).CXCL10, a member of the CXC chemokine subfamily, is a potent chemoattractant for mast cells and T lymphocytes, cells implicated in the pathophysiology of asthma and COPD. CXCL10 is elevated in the airways of asthmatic patients and has been implicated in mast cell migration to the ASM bundles (3Bradding P. Brightling Full Text Full Text PDF PubMed Scopus Google CXCL10 is elevated in the and of with which is largely steroid-resistant S. J. S. C.J. J. Immunol. PubMed Scopus Google CXCL10 has been in COPD S. J. J. PubMed Scopus Google Scholar, M. R.A. J. PubMed Scopus Google Scholar, M. M. P. S. A. J. PubMed Scopus Google and more has been reported that CXCL10 are increased to a in with asthma with and increased are of asthma exacerbations Johnston S.L. J. J. A. J. Allergy Clin. Immunol. Full Text Full Text PDF PubMed Scopus Google CXCL10 is in to IFNγ or TNFα from a of cell M. R.A. J. PubMed Scopus Google Scholar, S. M. M. J. J. Immunol. Google Scholar, A. M. R.A. J. Immunol. Google Scholar, A. PubMed Scopus Google Scholar, PubMed Scopus Google and that TNFα and IFNγ synergistically CXCL10 release J. S. P. PubMed Scopus Google Scholar, P. M. M. M. M. J. PubMed Google Scholar, S. P. S. J. Immunol. Google Scholar, S. P. S. J. PubMed Scopus Google the observed in asthma and the for is a to and an of the in transcription and of by ASM transcription factors binding to in J. 2005; PubMed Scopus Google Scholar, M. 2003; PubMed Scopus Google Scholar, J. 2003; Full Text Full Text PDF PubMed Scopus Google is in which to of transcription factors and RNA polymerase II. of an and that phosphorylation, which the and transcription PubMed Scopus Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar, PubMed Scopus Google Our of and transcription factors for these histone H4 acetylation as a in transcription M. 2003; PubMed Scopus Google Scholar, J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Immunol. 2005; PubMed Scopus Google Scholar, A. J. Immunol. PubMed Scopus Google is CXCL10 by transcription factors and histone in by and M. R.A. J. PubMed Scopus Google NF-κB in CXCL10 release but did not which transcription factors are by IFNγ although IFNγ a of no was observed with the NF-κB used in the a synergistic between TNFα and IFNγ on CXCL10 release but did not the TNFα has been reported to with IFNγ to synergistically induce M. A. J. Immunol. Google S. J. PubMed Scopus Google and PubMed Scopus Google although the are transcription factors in CXCL10 by IFNγ are and of are a of that are when cells such as and J. PubMed Google and to be for to and IFNγ Full Text Full Text PDF PubMed Scopus Google Scholar, J.M. M. Full Text Full Text PDF PubMed Scopus Google and J. Immunol. Google reported that the observed synergy between TNFα and IFNγ in between STAT-1α and NF-κB in and is by with or more of the transcription the but did not IFNγ or in with has been reported to a transcription factor that with STAT-1α and to on the promoter. of CXCL10 by NF-κB binding that NF-κB S. P. S. J. Immunol. Google Scholar, S. P. S. J. PubMed Scopus Google of the was to the transcription histone and RNA polymerase recruitment to the CXCL10 to at which of synergism be between TNFα and We that TNFα activates the classical NF-κB pathway, IFNγ via and synergism on CXCL10 is not to on transcription factor or histone but a effect on the recruitment of the coactivator and RNA polymerase II. We that inhibition of the signaling pathway may be a to steroid-resistant disease. is the in airway cells and a for the of airway

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