Calcium influx and the Ca2+-calmodulin complex are involved in interferon-gamma-induced expression of HLA class II...

Interferon gamma (IFN-gamma) induces HLA-DR and -DQ molecules and causes an accumulation of transcripts in HL-60 cells. Experiments were, therefore, designed to investigate the intracellular signaling molecules regulating the appearance of HLA class II molecules. The expression of HLA class II (DR and DQ) molecules induced by IFN-gamma was blocked by a calmodulin antagonist, W7, but not by a protein kinase C inhibitor, H7. Furthermore, a direct activator of protein kinase C, phorbol 12-myristate 13-acetate, was unable to induce HLA class II (DR) molecule expression. These results suggest that IFN-gamma induces HLA class II molecules on HL-60 cells by way of a calcium-calmodulin pathway and not by way of a protein kinase C pathway. Calmodulin is activated by a transient rise in the cytosolic free calcium. In fact, IFN-gamma evoked a calcium influx into HL-60 cells, whereas depletion of Ca2+ from culture medium resulted in a failure of IFN-gamma to induce DR expression. Furthermore, the calcium ionophore A23187 by itself induced DR molecule expression. These results suggest that IFN-gamma stimulates calcium influx by a so-called receptor-mediated calcium channel and activates the calmodulin branch of the calcium messenger system, resulting in the induction of DR molecules on the surface of HL-60 cells.