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Am J Physiol Lung Cell Mol Physiol 284: L1063-L1071, 2003. First published February 14, 2003; doi:10.1152/ajplung.00363.2002
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Vol. 284, Issue 6, L1063-L1071, June 2003

IFN-gamma inhibits human airway smooth muscle cell proliferation by modulating the E2F-1/Rb pathway

Yassine Amrani1, Omar Tliba1, Divaker Choubey2, Chien-Da Huang1, Vera P. Krymskaya1, Andrew Eszterhas1, Aili L. Lazaar1, and Reynold A. Panettieri Jr.1

1 Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104; and 2 Department of Radiation Oncology, Stritch School of Medicine, Loyola University Medical Center, Maywood, Illinois 60153

Elucidating the factors that inhibit the increase in airway smooth muscle (ASM) mass may be of therapeutic benefit in asthma. Here, we investigated whether interferon-gamma (IFN-gamma ), a potent inducer of growth arrest in various cell types, regulates mitogen-induced ASM cell proliferation. IFN-gamma (1-100 U/ml) was found to markedly decrease both DNA synthesis and ASM cell number induced by the mitogens epidermal growth factor (EGF) and thrombin. Interestingly, IFN-gamma had no effect on mitogen-induced activation of three major mitogenic signaling pathways, phosphatidylinositol 3-kinase, p70S6k, or mitogen-activated protein kinases. Mitogen-induced expression of cell cycle regulator cyclin D1 was increased by IFN-gamma , whereas no effect was observed on degradation of p27Kip1. Expression array analysis of 23 cell cycle-related genes showed that IFN-gamma inhibited EGF-induced increases in E2F-1 expression, whereas induction of c-myc, cyclin D2, Egr-1, and mdm2 were unaffected. Induction of E2F-1 protein and Rb hyperphosphorylation after mitogen stimulation was also suppressed by IFN-gamma . In addition, IFN-gamma decreased activation of cdk2 and expression of cyclin E, upstream signaling molecules responsible for Rb hyperphosphorylation in the late G1 phase. IFN-gamma also increased levels of IFI 16 protein, whose mouse homolog p202 has been associated with growth inhibition. Together, our data indicate that IFN-gamma is an effective inhibitor of ASM cell proliferation by blocking transition from G1-to-S phase by acting at two different levels: modulation of cdk2/cyclin E activation and inhibition of E2F-1 gene expression.

cytokines; airway remodeling; signal transduction; airway smooth muscle hyperplasia


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