Interferon-gamma-induced astrocyte class II major histocompatibility complex gene expression is associated with both protein kinase C activation and Na+ entry.
Astrocytes can be induced by interferon-gamma (IFN-gamma) to express class II major histocompatibility complex (MHC) antigens. This study was undertaken to elucidate the intracellular signaling pathways involved in IFN-gamma induction of class II MHC. We examined the effects of Na+/H+ antiporter and protein kinase C (PKC) inhibitors on class II expression and Na+ influx in astrocytes. We found that amiloride and ethyl isopropylamiloride, inhibitors of Na+/H+ exchange, blocked IFN-gamma-induced class II gene expression. IFN-gamma stimulated Na+ influx, and this increased influx was inhibited by amiloride. Treatment of astrocytes with the PKC inhibitor H7 also blocked the increase in Na+ uptake induced by IFN-gamma, indicating that IFN-gamma-induced PKC activation is required for subsequent Na+ influx. IFN-gamma treatment produced an increase of total PKC activity, which was associated with a rapid translocation of PKC activity from cytosolic to particulate fraction. H7 and another PKC inhibitor, staurosporine, inhibited IFN-gamma-induced class II gene expression. However, 4 beta-phorbol 12 beta-myristate 13 alpha-acetate, a potent PKC activator, did not affect class II expression. Taken together, our data indicate that both IFN-gamma-induced PKC activation and Na+ influx are required for class II MHC expression in astrocytes but that activation of PKC alone is not sufficient for ultimate expression of this gene.
Department of Neurology, University of Alabama, Birmingham 35294.
E N
EN
Benveniste
M
M
Vidovic
R B
RB
Panek
J G
JG
Norris
A T
AT
Reddy
D J
DJ
Benos
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001692:Biological Transport; D015152:Blotting, Northern; D004789:Enzyme Activation; D015870:Gene Expression; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism*
D000949:Histocompatibility Antigens Class II; D012333:RNA, Messenger; D000584:Amiloride; D007371:Interferon-gamma; D012964:Sodium; D011493:Protein Kinase C