SYNERGISM BETWEEN INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA INTHE 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 atheroscleros is. The effect of combinations of interleukin 1 (IL-1), 6 (IL-6), and 11 (IL-11), interferon gamma (IFN-gamma), leukaemia inhibitory factor (LIF) and tumour necrosis factor alpha (TNF-alpha) on the expression o f LPL in macrophages was studied using the murine J774.2 cell line. Th e suppression of heparin-releasable LPL activity produced by combinati ons of IL-1 and IL-11, IL-1 and TNF-alpha, IL-11 and TNF-alpha, and, I L-11 and IFN-gamma was substantially lower than that expected from the additive action of the corresponding two cytokines. By contrast, co-e xposure of cells to LIF and IFN-gamma, IL-6 and LIF, and, IFN-gamma an d TNF-alpha resulted in a more than additive, synergistic, suppression of LPL activity with the maximum reduction and maximum degree of syne rgism produced by combinations of IFN-gamma and TNF-alpha. The synergi sm between IFN-gamma and TNF-alpha was observed over a range of comple mentary dose combinations and also occurred when the cells were expose d first to IFN-gamma (priming), washed, and then stimulated subsequent ly with TNF-alpha. The reduction in LPL activity by combinations of IF N-gamma and TNF-alpha and the priming action of IFN-gamma were accompa nied by a comparable decrease in LPL mRNA concentrations, thereby indi cating that the major control responsible for the changes in LPL activ ity was being exerted at the level of mRNA metabolism (decreased trans cription 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 cytok ine. (C) 1997 Academic Press Limited.