SYNERGISM BETWEEN INTERFERON γ AND TUMOUR NECROSIS FACTOR α IN THE REGULATION OF LIPOPROTEIN LIPASE IN THE MACROPHAGE J774.2 CELL LINE

Abstract

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 (IFN-γ), leukaemia inhibitory factor (LIF) and tumour necrosis factor alpha (TNF-α) 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-α, IL-11 and IFN-γ 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-γ, IL-6 and LIF, and IFN-γ and TNF-α 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-γ and TNF-α. The synergism between IFN-γ and TNF-α was observed over a range of complementary dose combinations and also occurred when the cells were exposed first to IFN-γ (priming), washed, and then stimulated subsequently with TNF-α. The reduction in LPL activity by combinations of IFN-γ and TNF-α and the priming action of IFN-γ 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.