Regulation of IL-18 production by IFN gamma and PGE2 in mouse microglial cells: involvement of NF-kB pathway in the regulatory processes.
Interleukin (IL)-18, a recently identified proinflammatory cytokine, has been implicated in a variety of pathological conditions such as rheumatoid arthritis, insulin-dependent diabetes mellitus, and inflammatory liver injury. Microglial cells are the primary cellular source of IL-18 in the brain. Along with other inflammatory mediators in the central nervous system (CNS), IL-18 may play an important role in the pathogenesis of various neurodegenerative diseases. To understand how lymphokines and lipid mediators participate in the regulation of microglial IL-18 production, we assessed the effects of interferon (IFN)gamma, one of the major macrophage-activating lymphokines, and prostaglandin (PG)E(2), a lipid mediator produced in the brain, on IL-18 production and the expression of the IL-18 processing enzyme, caspase-1, in mouse microglial cells. IFNgamma increased lipopolysaccharide (LPS)-induced IL-18 production and caspase-1 expression, while PGE(2) inhibited LPS-induced IL-18 production. A similar pattern of IL-18 regulation by IFNgamma and PGE(2) was observed at the mRNA level. The regulation of microglial activation by IFNgamma and PGE(2) was accompanied by differential modulation of LPS-induced NF-kB activation. While IFNgamma enhanced LPS-induced NF-kB activation, PGE(2) suppressed its activation. These results indicate that IFNgamma and PGE(2) are the important regulators of proinflammatory microglial activation in CNS, and suggest the involvement of NF-kB pathway in these regulatory processes.
Suk
K
K
Department of Herbal Pharmacology, Graduate School of East-West Medical Science, Kyunghee University, Hoegi-dong, Tongdaemun-ku, 130-701, Seoul, South Korea. ksuk@nms.kyunghee.ac.kr
Yeou Kim
S
S
Kim
H
H
D000818:Animals; D000831:Animals, Newborn; D020170:Caspase 1 / Q000096:biosynthesis; D002460:Cell Line; D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology
D020382:Interleukin-18; D008070:Lipopolysaccharides; D016328:NF-kappa B; D007371:Interferon-gamma; D020170:Caspase 1; D015232:Dinoprostone