DIFFERENTIAL REGULATION OF LIPOPROTEIN-LIPASE IN THE MACROPHAGE J774.2 CELL-LINE BY CYTOKINES

The regulation of macrophage lipoprotein lipase (LPL) by cytokines is of potentially crucial importance in the pathogenesis of atheroscleros is and in the responses to endotoxin challenge. However, the precise m echanisms by which different cytokines modulate the expression of macr ophage LPL activity are poorly understood. The action of six cytokines and bacterial lipopolysaccharide (LPS) on LPL function using the muri ne J774.2 cell line as a model system has, therefore, been studied. Al though exposure to LPS, interleukin 11 (IL-11), tumour necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma) and IL-1, over the ph ysiological range of concentrations, resulted in a decrease in the hep arin-releasable LPL activity, LPL-mRNA levels and LPL-protein content of the cells, stimulation with IL-6 and leukaemia inhibitory factor (L IF) had no effect. The maximum suppression of LPL activity and mRNA le vels in the cells by IFN-gamma (60%) was lower than that produced by L PS, IL-11, TNF-alpha and IL-1 (78-97%). Each cytokine displayed a char acteristic dose-dependent pattern for the suppression of LPL activity and mRNA levels with IL-11-TNF-alpha being more potent than IFN-gamma/ IL-1. More than 80% of the decrease in the LPL activity, at all doses of IL-11, TNF-alpha, IFN-gamma and IL-1, was due to a corresponding re duction in the mRNA levels. The time course of responses to LPS, IL-11 , TNF-alpha, IFN-gamma and IL-1 were similar, with the time required t o achieve half maximal suppression of LPL activity being between 7 and 9.5 h in each case. These results indicate that LPL in J774.2 macroph ages is regulated differentially by various cytokines and that the maj or control responsible for the reduction of LPL activity by IL-11, TNF -alpha, IFN-gamma and IL-1 is exerted at the level of mRNA metabolism (decreased transcription or RNA stability). The responses identified a lso displayed several differences to those described previously for ad ipocytes (e.g. 3T3-L1 cell line), thereby suggesting the existence of potential cell-specific mechanisms for the regulation of LPL by cytoki nes. (C) 1996 Academic Press Limited