Effect of rottlerin, a PKC-delta inhibitor, on TLR-4-dependent activation of murine microglia.
In microglia, Toll-like receptors have been shown to recognize pathogen-associated molecular patterns and initiate innate immune responses upon interaction with infectious agents. The effect of rottlerin, a PKC-delta specific inhibitor, on TLR-4-mediated signaling was investigated in murine microglia stimulated with lipopolysaccharide and taxol. Pretreatment of microglia cells with rottlerin decreased LPS- and taxol-induced nitric oxide production in a concentration-dependent manner (IC50 = 99.1+/-1.5 nM). Through MTT and FACS analysis, we found that the inhibition effect of rottlerin was not due to microglial cell death. Rottlerin pretreatment also attenuated LPS-induced phosphorylation of IkappaB-alpha, nuclear translocation of NF-kappaB, and expression of type II nitric oxide synthase. In addition, microglial phagocytosis in response to TLR-4 activation was diminished in which rottlerin was pretreated. Together, these data raise the possibility that certain PKC-delta specific inhibitors can modulate TLR-4-derived signaling and inflammatory target gene expression, and can alter susceptibility to microbial infection and chronic inflammatory diseases in central nervous system.
Kim
Dong-Chan
DC
Division of Molecular and Life Science, SBD-NCRC, Pohang University of Science and Technology, Pohang, Republic of Korea.
Kim
Sun-Hee
SH
Jeong
Min-Woo
MW
Baek
Nam-In
NI
Kim
Kyong-Tai
KT
D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010587:Phagocytosis / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051745:Protein Kinase C-delta; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009569:Nitric Oxide; C085746:rottlerin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta