Regulation of IL-18 production by IFNγ and PGE 2 in mouse microglial cells: involvement of NF-kB pathway in the regulatory processes

Abstract

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)γ, 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. IFNγ 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 IFNγ and PGE 2 was observed at the mRNA level. The regulation of microglial activation by IFNγ and PGE 2 was accompanied by differential modulation of LPS-induced NF-kB activation. While IFNγ enhanced LPS-induced NF-kB activation, PGE 2 suppressed its activation. These results indicate that IFNγ 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.