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

Alaina J. Ammit, Aili L. Lazaar, Carla Irani, Geraldine M. O'Neill, Nancy D. Gordon, Yassine Amrani, Raymond B. Penn, Reynold A. Panettieri

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

Abstract

Recent studies have demonstrated that tumor necrosis factor (TNF)-α 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-α induced IL-6 gene expression in ASM cells via a nuclear factor (NF)-κB-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-α-induced IL-6 secretion was only partially inhibited by dexamethasone, yet TNF-α-induced RANTES secretion was abolished. β-Agonists induced IL-6 secretion from ASM via activation of the CRE region of the IL-6 promoter. β-Agonists augmented TNF-α-induced IL-6 secretion, reflecting an additive effect of NF-κB and CRE response elements on IL-6 gene expression. In contrast, β-agonists inhibited TNF-α-induced RANTES secretion via an AP-1-independent pathway. Collectively, these data elucidate transcriptional mechanisms mediating TNF-α-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.

Original languageEnglish (US)
Pages (from-to)465-474
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume26
Issue number4
DOIs
StatePublished - 2002

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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