Interferon-gamma induces secretory group IIA phospholipase A2 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. However, the factors controlling sPLA(2)-IIA production in human vascular cells are unknown. We investigated regulation of sPLA(2)-IIA expression and secretion by human arterial smooth muscle cells in culture (HASMC). SPLA(2)-IIA was induced after 3-14 days of culture in non-proliferating conditions. SPLA(2)-IIA was co-expressed with heavy caldesmon, a cytoskeleton protein, and p27, a G(1) cyclin inhibitor, proteins characteristically expressed by differentiated cells. Further incubation with 50-500 units/ml of interferon (IFN)-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 with cell membrane proteoglycans. IFN-gamma induced sPLA(2)-IIA expression was antagonized by tumor necrosis factor (TNF)-alpha and interleukin (IL)-10. TNF-alpha added individually induced a significant but transient (4 h) increase in sPLA(2)-IIA secretion. IL-10 by itself did not affect sPLA(2)-IIA expression and secretion. IFN-gamma-stimulated sPLA(2)-IIA transcription involved STAT-3 protein. Interestingly, IL-6 but not IFN-gamma up-regulated the 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 secretion. This IFN-gamma stimulatory effect can be modulated by other cytokines.
Peilot
H
H
Wallenberg Laboratory for Cardiovascular Disease, Sahlgrenska University Hospital, Göteborg 413 45, Sweden.
Rosengren
B
B
Bondjers
G
G
Hurt-Camejo
E
E
D001158:Arteries / Q000166:cytology / Q000201:enzymology*; D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004790:Enzyme Induction; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D010641:Phenotype; D010741:Phospholipases A / Q000096:biosynthesis* / Q000235:genetics; D054467:Phospholipases A2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation
D017931:DNA Primers; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma; D010741:Phospholipases A; D054467:Phospholipases A2