Am. J. Respir. Cell Mol. Biol., Volume 26, Number 4, April, 2002 465-474

Tumor Necrosis Factor--Induced Secretion of RANTES and Interleukin-6 from Human Airway Smooth Muscle Cells
Modulation by Glucocorticoids and -Agonists

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

Faculty of Pharmacy, University of Sydney, Sydney, Australia; Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Oncology Research Unit, Children's Hospital at Westmead, Westmead, Australia; and Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania

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

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