Differential regulation of IL-1α and TNFα release from immortalized murine microglia (BV-2)

Microglia, the resident macrophages of the brain, secrete a number of mediators involved in neural-immune function. The cytokines, IL-1α and TNFα, are two such factors which are stored as inactive precursor molecules requiring post-translational preteolytic processing prior to release. From investigations of second messenger pathways involved in regulating the secretion of these cytokines, we have demonstrated that the PKC inhibitor, H-7, blocks the induction of TNFα secretion induced by LPS. In contrast, H-89 and HA-1077, inhibitors of cyclic nucleotide-dependent protein kinases (PKA and PKG), did not alter LPS-stimulation of TNFα release. Consistent with these observations, the weak PKC activator, mezerein, induced TNFα secretion in an H-7-reversible manner. In marked contrast, PKC activation did not induce IL-1α secretion and H-7 potentiated IL-1α release. In the case of the protein phosphatase inhibitor, okadaic acid, secretion of both cytokines was induced, indicating that protein phosphorylation is important for the induction of cytokine secretion but only in the case of TNFα is PKC involved. In the case of IL-1α, a tonic inhibitory regulation involving PKC activation may be present. We therefore conclude that alterations in phosphorylation-dephosphorylation cycles may be important triggers in the switching of microglial cellular function from a resting to an activated state.