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Am J Physiol Lung Cell Mol Physiol (February 14, 2003). doi:10.1152/ajplung.00363.2002
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Submitted on October 29, 2002
Accepted on January 28, 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, Jr1

1 Department of Medicine, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, PA, USA
2 Department of Radiation Oncology, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL, USA

* To whom correspondence should be addressed. E-mail: amran{at}mail.med.upenn.edu.

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 EGF and thrombin. Interestingly, IFN{gamma} had no effect on mitogen-induced activation of three major mitogenic signaling pathways, PI3-kinase, p70S6k or mitogen activated protein kinases (MAPKs). Mitogen-induced expression of cell cycle regulator cyclin D1 was increased by IFN{gamma} while 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 while induction of c-myc, cyclin D2, Egr-1 and mdm2 were unaffected. Induction of E2F-1 protein and Rb hyper-phosphorylation following 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 hyper-phosphorylation in the late G1 phase. IFN{gamma} also increased levels of IFI 16 protein, whose mouse homologue 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/cyclinE activation and inhibition of E2F-1 gene expression.




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