INVOLVEMENT OF BOTH THE TYROSINE KINASE AND THE PHOSPHATIDYLINOSITOL-3′ KINASE SIGNAL TRANSDUCTION PATHWAYS IN THE REGULATION OF LIPOPROTEIN LIPASE EXPRESSION IN J774.2 MACROPHAGES BY CYTOKINES AND LIPOPOLYSACCHARIDE

The regulation of macrophage lipoprotein lipase (LPL) by cytokines and lipopolysaccharide (LPS) is of potentially crucial importance in the pathogenesis of atherosclerosis and in the responses to endotoxin challenge. We show here that the reduction of LPL activity in J774.2 macrophages observed in the presence of interleukin (IL-1) and IL-11 was sensitive to herbimycin A, with the effect of LPS, interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) on LPL activity being sensitive to both herbimycin A and wortmannin. The action of the inhibitors on the IFN-γ-dependent reduction of LPL activity was mediated at the level of LPL mRNA metabolism, with translational and/or post-translational levels of regulation being involved in the action of all the other mediators tested. These observations suggest that both the tyrosine kinase and the phosphatidylinositol-3′-kinase signalling pathways are involved in the suppression of macrophage LPL expression by LPS and cytokines.