PT - JOURNAL ARTICLE AU - Elena A. Goncharova AU - Dmitry A. Goncharov AU - Amelia Chisolm AU - Matthew S. Spaits AU - Poay N. Lim AU - Gregory Cesarone AU - Irene Khavin AU - Omar Tliba AU - Yassine Amrani AU - Reynold A. Panettieri, Jr. AU - Vera P. Krymskaya TI - Interferon β Augments Tuberous Sclerosis Complex 2 (TSC2)-Dependent Inhibition of TSC2-Null ELT3 and Human Lymphangioleiomyomatosis-Derived Cell Proliferation AID - 10.1124/mol.107.040824 DP - 2008 Mar 01 TA - Molecular Pharmacology PG - 778--788 VI - 73 IP - 3 4099 - http://molpharm.aspetjournals.org/content/73/3/778.short 4100 - http://molpharm.aspetjournals.org/content/73/3/778.full SO - Mol Pharmacol2008 Mar 01; 73 AB - Lymphangioleiomyomatosis (LAM), a rare pulmonary disorder, manifests as an abnormal neoplastic growth of smooth muscle-like cells within the lungs. Mutational inactivation of tumor suppressor tuberous sclerosis complex 2 (TSC2) in LAM constitutively activates the mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) signaling pathway and promotes neoplastic growth of LAM cells. In many cell types, type I interferon β (IFNβ) inhibits proliferation and induces apoptosis through signal transducers and activators of transcription (STAT)-dependent and STAT-independent signaling pathways, one of which is the mTOR/S6K1 signaling pathway. Our study shows that IFNβ is expressed in LAM tissues and LAM-derived cell cultures; however, IFNβ attenuates LAM-derived cell proliferation only at high concentrations, 100 and 1000 U/ml (IC50 value for IFNβ is 20 U/ml compared with 1 U/ml for normal human mesenchymal cells, human bronchus fibroblasts and human airway smooth muscle cells). Likewise, IFNβ only attenuates proliferation of smooth muscle TSC2-null ELT3 cells. Analysis of IFNβ signaling in LAM cells showed expression of IFNβ receptor α (IFNβRα) and IFNβRβ, activation and nuclear translocation of STAT1, and phosphorylation of STAT3 and p38 mitogen-activated protein kinase (MAPK), but IFNβ had little effect on S6K1 activity. However, the re-expression of TSC2 or inhibition of mTOR/S6K1 with rapamycin (sirolimus) augmented antiproliferative effects of IFNβ in LAM and TSC2-null ELT3 cells. Our study demonstrates that IFNβ-dependent activation of STATs and p38 MAPK is not sufficient to fully inhibit proliferation of cells with TSC2 dysfunction and that TSC2-dependent inhibition of mTOR/S6K1 cooperates with IFNβ in inhibiting human LAM and TSC2-null ELT3 cell proliferation. The American Society for Pharmacology and Experimental Therapeutics