Biphasic modulation of intracellular Ca2+ concentration by interleukin-1beta in cortical synaptosomes: involvement of a pertussis toxin-sensitive G-protein and mitogen-activated protein kinase.

The modulation of intracellular Ca2+ concentration ([Ca2+]i) by the pro-inflammatory cytokine interleukin-1beta (IL-1beta) was assessed in synaptosomes loaded with the Ca2+-sensitive dye, Fura-2AM. IL-1beta was found to exert a biphasic effect on the KCl-induced rise in [Ca2+]i, extending an inhibitory effect at lower (3.5 ng/ml) concentrations, and a stimulatory effect at high (100 ng/ml) concentrations. The inhibitory action of IL-1beta on [Ca2+]i was sensitive to pertussis toxin (PTX; 2 microg/ml), indicating a role for a PTX-sensitive G-protein, but was unaffected by the p42 mitogen-activated protein kinase kinase (MAP kinase kinase) inhibitor, PD 098059 (2 microM). In contrast, the stimulatory action of higher concentrations of IL-1beta on [Ca2+]i was blocked by PD 098059 and unaffected by PTX. We conclude that the biphasic actions of IL-1beta on the KCl-induced rise in [Ca2+]i are mediated through activation of alternative second messenger pathways.