Differential regulation of IL-1 alpha and TNF alpha 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-1 alpha and TNF alpha, are two such factors which are stored as inactive precursor molecules requiring post-translational proteolytic 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 TNF alpha 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 TNF alpha release. Consistent with these observations, the weak PKC activator, mezerein, induced TNF alpha secretion in an H-7-reversible manner. In marked contrast, PKC activation did not induce IL-1 alpha secretion and H-7 potentiated IL-1 alpha 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 TNF alpha is PKC involved. In the case of IL-1 alpha, 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.
Wood
P L
PL
Department of Pharmacology, CoCensys, Inc., Irvine, CA 92718.
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D002460:Cell Line; D004224:Diterpenes; D004988:Ethers, Cyclic / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019319:Okadaic Acid; D010431:Pentoxifylline / Q000494:pharmacology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D013729:Terpenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D004224:Diterpenes; D004988:Ethers, Cyclic; D007375:Interleukin-1; D007546:Isoquinolines; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D010879:Piperazines; D013729:Terpenes; D014409:Tumor Necrosis Factor-alpha; D019319:Okadaic Acid; C011309:mezerein; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D010431:Pentoxifylline