Interferon gamma inhibits both proliferation and expression of differentiation-specific alpha-smooth muscle actin in arterial smooth muscle cells.

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Abstract
Differentiation of muscle cells is characterized morphologically by the acquisition of contractile filaments and characteristic shape changes, and on the molecular level by induction of the expression of several genes, including those for the muscle-specific .alpha.-actin isoforms. IFN-.gamma. is an inhibitor of proliferation for several cells, including vascular smooth muscle, and is also an inducer of differentiated properties for several hematopoietic cells. We have therefore investigated whether IFN-.gamma. affects the expression of .alpha.-smooth muscle actin in cultured arterial smooth muscle cells. Cells exposed to IFN-.gamma. show a reduction of .alpha.-smooth muscle actin-containing stress fibers, as detected by immunofluorescence. The effect was observed in all phases of the cell cycle, and was caused by a reduction of the synthesis of .alpha.-smooth muscle actin protein as revealed by two-dimensional electrophoretic analysis of actin isoforms. RNA hybridization using a cRNA probe that hybridizes to all actin mRNAs showed that IFN-.gamma.-treated cells have a reduced content of the 1.7-kb mRNA that codes for .alpha.-smooth muscle actin, and to a lesser extent, also of the 2.1-kb mRNA encoding the .beta. and .gamma.-cytoplasmic actins. The reduction of .alpha.-smooth muscle actin mRNA was confirmed using an .alpha.-smooth muscle actin-specific cRNA probe. The reduction of .alpha.-smooth muscle actin mRNA occurs within 12 h, and is dependent on protein synthesis, since cycloheximide treatment reversed the effect. The inhibition of this mRNA species was dose dependent, and detectable by RNA hybridization at a dose of 50 U/ml IFN-.gamma.. These results suggest that the differentiation of arterial smooth muscle cells is not necessarily coupled to an inhibition of cellular proliferation. Instead, IFN-.gamma. may regulate the expression of several genes that control both proliferation and expression of differentiation markers.