Early Steps in Interferon-γ Production: Possible Involvement of Ca2+-CalmodulinDependent Enzymes

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Abstract
A23187 in combination with phorbol myristate acetate (PMA) strongly induces production of interferon-γ (IFN-γ) by human peripheral blood mononuclear cells (PBMC) and even by murine PBMC, which respond poorly to A23187 alone. Macrophage depletion of PBMC strongly reduces IFN-γ production induced by several mitogens, but does not affect IFN-γ production induced by A23187 and PMA. In addition the same stimuli are able in combination to induce strong amounts of IFN-γ, even in the Jurkat T cell line. The protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7) and the calmodulin antagonist N-(6-aminoehexyl)-5-chloro-1-naphthalenesulfonamide (W-7) were examined for their ability to inhibit IFN-γ production induced by PMA and A23187. At concentrations near the Ki for protein kinase C, H-7 failed to inhibit PMA-and A23187-induced IFN-γ production. In contrast, W-7 at low concentrations inhibited IFN-γ production induced by the same stimuli. In addition OAG, which is known to directly activate protein kinase C, failed to act synergistically with A23187 in the induction of IFN-γ. On the basis of these results we propose that A23187 and PMA may mimic the early steps of lymphocyte activation, without the requirement of macrophage, bypassing antigen-, or lectin-induced signal. Our results suggest that Ca2+-calmodulin-dependent reactions other than protein kinase C activation may be essential for IFN-γ production, at least at level of the producing cells.