Abstract

Cyclosporine-A (CyA) and FK506 are immunosuppressive agents that are widely used to treat inflammatory and autoimmune disorders because of their ability to suppress the production of Th1 cytokines including IL-12. Both CyA and FK506 are potent inhibitors of calcineurin in the calcium signalling pathway. However, the role of calcium signalling in the regulation of human IL-12p40 production remains unknown. Interestingly, calcium and phosphoinositide 3-kinase (PI3K) signalling pathways have been shown to negatively regulate LPS-induced murine IL-12p40 production. Contrary to these observations, we show here that LPS-induced IL-12p40 production in human monocytic cells is positively regulated by calcium activated calmodulin- (CaM) and CaM-dependent protein kinase-II (CaMK-II)-activated PI3K. Furthermore, LPS induced the production of IL-12p40 by NFκB and AP-1 transcription factors through the activation of upstream CaM/CaMK-II. LPS-induced IL-12p40 production is known to be regulated by the c-Jun-N-terminal kinase (JNK) pathway. Importantly, both CyA and FK506 downregulated LPS-induced IL-12p40 transcription by inhibiting CaM/CaMK-II-activated PI3K and their downstream transcription factors NFκB and AP-1 independent of the JNK pathway.

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