Effect of IL-1beta on CRE-dependent gene expression in human airway smooth muscle cells.

Lahiri T, Moore PE, Baraldo S, Whitehead TR, McKenna MD, Panettieri RA, Shore SA
Am J Physiol Lung Cell Mol Physiol. 2002 283 (6): L1239-46

PMID: 12388341 · DOI:10.1152/ajplung.00231.2001

IL-1beta inhibits isoproterenol (ISO)-induced relaxation of cultured human airway smooth muscle (HASM) cells. The purpose of this study was to determine whether IL-1beta can also suppress ISO-induced cAMP response element (CRE)-dependent gene expression. ISO (10 microM) caused a marked increase in CRE-binding protein (CREB) phosphorylation, which was attenuated by IL-1beta (2 ng/ml). This effect of IL-1beta was abolished by the cyclooxygenase (COX) inhibitor indomethacin. To examine CRE-driven gene expression, we transiently transfected HASM cells with a construct containing CRE upstream of a luciferase reporter gene. ISO (6 h) caused a sixfold increase in luciferase activity. IL-1beta (24 h) alone also increased luciferase activity, although to a lesser extent (2-fold). However, the ability of ISO to elicit luciferase expression was markedly reduced in cells treated with IL-1beta. Indomethacin, the MEK and p38 inhibitors U-0126 and SB-203580, the protein kinase A inhibitor H-89, and dexamethasone each completely abolished the ability of IL-1beta to induce CRE-driven gene expression but only slightly increased the ability of ISO to induce CRE-driven gene expression in IL-1beta-treated cells. IL-1beta also attenuated dibutyryl cAMP-induced CRE-driven gene expression, but not dibutyryl cAMP-induced CREB phosphorylation. Tumor necrosis factor-alpha (10 ng/ml) also attenuated ISO-induced CRE-driven gene expression, even though it was without effect on ISO-induced cAMP formation or ISO-induced CREB phosphorylation. The results suggest that IL-1beta and tumor necrosis factor-alpha may attenuate the ability of beta-agonists to induce expression of genes with CRE in their regulatory regions at least in part through events downstream of CREB phosphorylation.

MeSH Terms (16)

Adrenergic beta-Agonists Bucladesine Cells, Cultured Cyclic AMP Cyclic AMP Response Element-Binding Protein Gene Expression Humans Interleukin-1 Interleukin-6 Isoproterenol Muscle, Smooth Phosphorylation Promoter Regions, Genetic Response Elements Trachea Tumor Necrosis Factor-alpha

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