The inflammatory cytokines interleukin-1 (IL-1Elevated plasma levels of cytokines, including IL-1 and TNF found in various inflammatory, infectious, and malignant diseases, are often associated with hypocholesterolemia (7-11). Systemic infusion of cytokines has been shown to lower serum cholesterol levels in animals and humans (12-14). The concentrations of IL-1 and TNF similar to those found following infection induce low density lipoprotein (LDL) receptor expression in human hepatoma (HepG2) cells, and this effect is not part of its mitogenic response, as IL-1 did not increase DNA synthesis (15-18). Interestingly, a 1.56-kilobase pair region of the 5Ј-flanking region of the human LDL receptor promoter has been shown to confer IL-1-dependent induction to an heterologous gene, suggesting that increased receptor expression results from activation of LDL receptor transcription and is not due to an alteration in LDL receptor mRNA stability (18). These studies have also established that, unlike TNF, IL-1-induced LDL receptor transcription does not require protein synthesis and, therefore, likely depends on activation of a preexisting component(s). The initial step in their action is the association of agonist with its cell surface receptors, followed by intracellular protein phosphorylation/dephosphorylation (19 -21). The downstream effectors linking receptor activation with the different cellular responses are still largely to be defined, although several signaling pathways have been proposed (20,21). The signal transduction mechanisms by which these cytokines stimulates LDL receptor expression are poorly characterized. Many extracellular signals elicit specific biological responses through activation of MAPK cascades (22-26). The three major subfamilies of MAPKs in higher eukaryotes include ERK-1/2, 46/54 JNK , and p38 MAPK , all of which are activated by phosphorylation of a tyrosine and a threonine residue catalyzed by a dual specificity MAPK kinase. ERKs are most strongly activated by mitogenic signals such as growth factors or 12-Otetradecanoylphorbol-13-acetate (TPA), whereas p46/54 JNK , and p38MAPK are activated by stressful stimuli such as the inflammatory cytokines, IL-1, and TNF, thermal shock, and osmotic shock (23,27). Activation of MAPKs leads to distinct cellular responses mediated by phosphorylation of specific target substrates (25). Recently, we have shown involvement of ERK-1/2 signaling cascade in TPA-induced LDL receptor expression in HepG2 cells (28).In this study, we have investigated the early in vivo signal-