Calcium influx and the Ca2+-calmodulin complex are involved in interferon-gamma-induced expression of HLA class II molecules on HL-60 cells.

Abstract

Interferon y (IFN-y) 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-y 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-y 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-y evoked a calcium influx into HL-60 cells, whereas depletion of Ca2+ from culture medium resulted in a failure of IFN-y to induce DR expression. Furthermore, the calcium ionophore A23187 by itself induced DR molecule expression. These results suggest that IFN-y stimulates calcium influx by a so-called receptor-mediated calcium channel and activates the calmodulin branch of the culcium messenger system, resulting in the induction of DR molecules on the surface of HL-60 cells.

Requirement of Ca2+and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-γ

“…UV, lipopolysaccharide, and tumor necrosis factor have been reported to induce Stat1 S727 phosphorylation without Y701 phosphorylation (12). Together with earlier observations that Ca 2ϩ ͞calmodulin is required for IFN-␥-induced MHCII expression (27) and lipopolysaccharide-stimulated inducible NO synthase (iNOS) production (39), these results suggest that signaling events that elicit Ca 2ϩ flux can result in Stat1 S727 phosphorylation, which is critical for Stat1-mediated gene activation. Ca 2ϩ is a ubiquitous messenger involved in a multitude of cellular processes (16).…”

“…IFN-␥ has been shown to elicit a Ca 2ϩ flux in certain cell types (27)(28)(29), suggesting a possible involvement of Ca 2ϩ flux in IFN-␥ signaling. However, its physiological consequence was not clear.…”

Effect of pteridine derivatives on intracellular calcium concentration in human monocytic cells

“…A number of mediators of the immune system have been reported to increase the intracellular calcium concentration, such as interferon-y [ 14,191, the cytokine-stimulating pteridine biosynthesis in human monocytes/macrophages [6]. An increase of intracellular calcium has in turn been shown to play an important role in the activation of human monocytic cells [9,10,14,19,20]. Accordingly, the ability of pteridine derivatives to increase the intracellular calcium concentration in human monocytic cells indicates that these macrophage-derived substances may be involved in the regulation of calcium-mediated macrophage activation.…”

Protein kinase C is crucial in signal transduction during IFN‐γ induction in endothelial cells

“…IFN-7 has been shown to operate via the calcium-calmodulin pathway, but not via protein kinase C in the HL-60 monocytic cell line [16]. Yet in two other monocytic cell lines, U 937 and in a lymphoid cell line YT-1, the protein kinase C pathway but not the calcium-dependent pathway was shown to be the route of signal transduction [16]. The discrepancy might be due to the fact that both these cell lines are malignant and the transformation might have caused alterations in the intracellular signal transduction mechanisms.…”