Essential role of NF-κB and AP-1 transcription factors in TNF-α-induced TSLP expression in human airway smooth muscle cells

Redhu NS, Saleh A, Halayko AJ, Ali AS, Gounni AS. Essential role of NF-kappa B and AP-1 transcription factors in TNF-alpha-induced TSLP expression in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 300: L479-L485, 2011. First published December 10, 2010; doi:10.1152/ajplung.00301.2009.-Human airway smooth muscle (HASM) cells are a rich source of inflammatory mediators that may propagate the airway inflammatory responses. Recent studies from our laboratory and others demonstrate that HASM cells express the proallergic cytokine thymic stromal lymphopoietin (TSLP) in vitro and in vivo. Compelling evidence from in vitro studies and animal models suggest that the TSLP is a critical factor sufficient and necessary to induce or maintain the allergic airway inflammation. Despite of an immense interest in pathophysiology of TSLP in allergic inflammation, the triggers and mechanisms of TSLP expression remain inadequately understood. In this study, we found that TNF-alpha upregulates the TSLP mRNA and induces high levels of TSLP protein release in primary human ASM cells. Interestingly, TNF-alpha induced the TSLP promoter activity (P < 0.05; n = 4) in HASM that was mediated by upstream NF-kappa B and activator protein-1 (AP-1) binding sites. Mutation in NF-kappa B and AP-1 binding sites completely abrogated the effect of TNF-alpha-mediated TSLP promoter activity and so did the expression of a dominant-negative mutant construct of I kappa B kinase. Furthermore, the peptide inhibitors of I kappa B kinase or NF-kappa B inhibited the TNF-alpha-induced TSLP protein release (P < 0.05; n = 3) in HASM. Collectively, our data suggest a novel important biological role for NF-kappa B pathway in TNF-alpha-induced TSLP expression in HASM and recommend this as a prime target for anti-inflammatory drugs.