Interferon-gamma induces secretory group IIA phospholipase A(2) in human arterial smooth muscle cells - Involvement of cell differentiation, STAT-3 activation, and modulation by other cytokines

Increased expression of secretory non-pancreatic phospholipase A(2) (sPLA(2 )-IIA) could be part of the inflammatory reaction in atherosclerosis. Howev er, the factors controlling sPLA(2)-IIA production in human vascular cells are unknown. We investigated regulation of sPLA(2)-IIA expression and secre tion by human arterial smooth muscle cells in culture (HASMC), SPLA(2)-IIA was induced after 3-14 days of culture in non-proliferating conditions. SPL A(2)-IIA was co-expressed with heavy caldesmon, a cytoskeleton protein, and p27, a G(1) cyclin inhibitor, proteins characteristically expressed by dif ferentiated cells, Further incubation with 50-500 units/mi of interferon (I FN)-gamma significantly increased sPLA(2)-IIA mRNA and secretion. IFN-gamma -induced sPLA(2)-IIA was found to be active in cell media and associated wi th cell membrane proteoglycans. IFN-gamma induced sPLA(2)-IIA expression wa s antagonized by tumor necrosis factor (TNF)-alpha and interleukin (n)-10, TNF-alpha added individually induced a significant but transient (4 h) incr ease in sPLA(2)-IIA secretion. IL-10 by itself did not affect sPLA(2)-IIA e xpression and secretion. IFN-gamma-stimulated sPLA(2)-IIA transcription inv olved STAT-3 protein. Interestingly, IL-6 but not IFN-gamma up-regulated th e sPLA(2)-IIA expression in HepG2 cells, thus sPLA(2)-IIA induction by IFN- gamma response appears to be cell specific. In summary, conditions leading to cell differentiation induced sPLA(2)-IIA expression in HASMC and further exposure to IFN-gamma can up-regulate sPLA(2)-IIA transcription and secret ion. This IFN-gamma stimulatory effect can be modulated by other cytokines.