Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth muscle cells: modulation by glucocorticoids and beta-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)-kappaB-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-kappaB and CRE response elements on IL-6 gene expression. In contrast, beta-agonists inhibited TNF-alpha-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 trans-acting elements that determine the differential effects of glucocorticoids and cAMP-elevating agents on the expression of these genes.
Ammit
Alaina J
AJ
Faculty of Pharmacy, University of Sydney, Sydney, Australia.
Lazaar
Aili L
AL
Irani
Carla
C
O'Neill
Geraldine M
GM
Gordon
Nancy D
ND
Amrani
Yassine
Y
Penn
Raymond B
RB
Panettieri
Reynold A
RA
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004347:Drug Interactions; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D014132:Trachea / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D018946:Chemokine CCL5; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D015850:Interleukin-6; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D000242:Cyclic AMP; D015232:Dinoprostone; D007545:Isoproterenol