Tumor necrosis factor-α-induced secretion of RANTES and interleukin-6 from human airway smooth muscle cells -: Modulation by glucocorticoids and β-agonists

Recent studies have demonstrated that tumor necrosis factor (TNF-alpha)- stimulates the secretion of interleukin (IL)-6 and regulated on activation, normal T cells expressed and secreted (RANTES) from airway smooth muscle (ASM) cells, with the induction of each molecule being differentially regulated (IL-6 increased, RANTES inhibited) by cyclic adenosine monophosphate (cAMP)-elevating agents. In this study we identify the mechanisms mediating IL-6 and RANTES gene transcription in human ASM cells. We found that TNF-alpha induced IL-6 gene expression in ASM cells via a nuclear factor (NF)-KB-dependent pathway, whereas RANTES gene expression was mediated via activation of activator protein (AP)-1 and nuclear factor of activated T cells (NF-AT). TNF-alpha-induced IL-6 secretion was only partially inhibited by dexamethasone, yet TNF-alpha-induced RANTES secretion was abolished. (beta-Agonists induced IL-6 secretion from ASM via activation of the CRE region of the IL-6 promoter. (beta-Agonists augmented TNF-alpha-induced IL-6 secretion, reflecting an additive effect of NF-KB and CRE response elements on IL-6 gene expression. In contrast, (3-agonists inhibited TNF-a-induced RANTES secretion via an AP-1-independent pathway. Collectively, these data elucidate transcriptional mechanisms mediating TNF-alpha-induced IL-6 and RANTES secretion from ASM cells, and identify the specific cis- or traps-acting elements that determine the differential effects of glucocorticoids and CAMP-elevating agents on the expression of these genes.