INDUCTION OF INTERLEUKIN-1 BETA-CONVERTING ENZYME (ICE) IN MURINE MICROGLIA BY LIPOPOLYSACCHARIDE

Interleukin-1 beta (IL-1 beta) synthesized in the brain is thought to be involved in the behavioral response to LPS. In this study, we exami ned in microglia the ability of LPS to induce interleukin-1 beta-conve rting enzyme (ICE), the protease responsible for processing proIL-1 be ta to its mature biologically active form. The murine microglial cell line, N13, and primary microglia which had been previously isolated fr om brains of 2-d-old endotoxin-responsive C3H/HeOuJ mice and endotoxin -resistant C3H/HeJ mice, were cultured in the presence of various conc entrations of LPS. Oligonucleotide primers for ICE and GAPDH were used in RT-PCR to determine the levels of ICE mRNA in microglia. ICE mRNA was constitutively expressed in N13 cells and primary microglia from b oth C3H/HeOuJ and C3H/HeJ mice. Upon exposure to LPS, ICE mRNA levels were markedly elevated in N13 cells and in microglia from C3H/HeOuJ mi ce, but not in microglia from endotoxin-resistant C3H/HeJ mice. Wester n immunoblotting was used to determine if the increase in ICE mRNA ind uced by LPS was accompanied by an increase in ICE protein. A modest in crease in immunoreactivity for the p45 ICE precursor protein was evide nt in N13 cells and primary microglia from C3H/HeOuJ mice following ex posure to LPS. Because corticosteroids inhibit the synthesis and secre tion of IL-1 beta, in a second experiment microglia were treated with LPS in the presence of dexamethasone (0, 10 and 100 mu M). Dexamethaso ne inhibited the LPS-induced increase in ICE mRNA and protein in micro glia from C3H/HeOuJ mice. These results indicate that LPS stimulates m icroglia to express ICE. That dexamethasone inhibited the expression o f ICE, suggests that corticosteroids regulate the secretion of IL-1 be ta by microglial cells, in part, by regulating the expression of ICE. (C) 1997 Elsevier Science B.V.