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Synergism between interferon gamma and tumour necrosis factor alpha in the regulation of lipoprotein lipase in the macrophage J774.2 cell line.

The regulation of macrophage lipoprotein lipase (LPL) by cytokines is of potentially crucial importance in the pathogenesis of atherosclerosis. The effect of combinations of interleukin 1 (IL-1), 6 (IL-6), and 11 (IL-11), interferon gamma (INF-gamma), leukaemia inhibitory factor (LIF) and tumour necrosis factor alpha (TNF-alpha) on the expression of LPL in macrophages was studied using the murine J774.2 cell line. The suppression of heparin-releasable LPL activity produced by combinations of IL-1 and IL-11, IL-1 and TNF-alpha, IL-11 and TNF-alpha, and, IL-11 and INF-gamma was substantially lower than that expected from the additive action of the corresponding two cytokines. By contrast, co-exposure of cells to LIF and IFN-gamma, IL-6 and LIF, and INF-gamma and TNF-alpha resulted in a more than additive, synergistic, suppression of LPL activity with the maximum reduction and maximum degree of synergism produced by combinations of IFN-gamma and TNF-alpha. The synergism between IFN-gamma and TNF-alpha was observed over a range of complementary dose combinations and also occurred when the cells were exposed first to INF-gamma (priming), washed, and then stimulated subsequently with TNF-alpha. The reduction in LPL activity by combinations of IFN-gamma and TNF-alpha and the priming action of IFN-gamma were accompanied by a comparable decrease in LPL mRNA concentrations, thereby indicating that the major control responsible for the changes in LPL activity was being exerted at the level of mRNA metabolism (decreased transcription or RNA stability). These results suggest that the modulation of macrophage LPL function in atherosclerosis by cytokine combinations may be more important than the presence or absence of any given cytokine.