INTERFERON-GAMMA OVERCOMES THE GLUCOCORTICOID-MEDIATED AND THE INTERLEUKIN-4-MEDIATED INHIBITION OF INTERLEUKIN-1-BETA SYNTHESIS IN HUMAN MONOCYTES

Interleukin-1 (IL-1) has been implicated in the tissue destruction of rheumatoid arthritis, a disease that is widely treated with glucocorti coids. In this study we investigated the effect of the T cell product interferon-gamma (IFN-gamma) on the glucocorticoid-mediated and on the IL-4-mediated inhibition of IL-1beta mRNA and IL-Ibeta protein synthe sis in highly purified human monocytes. Both dexamethasone and IL-4 do se-dependently inhibited IL-1beta mRNA and IL-1beta protein synthesis after stimulation with LPS (300 ng/ml); maximal inhibition of 80-90% w as achieved. IFN-gamma (1-100 U/ml) did not influence lL-1beta mRNA an d IL-1beta protein levels in unstimulated cells, but potentiated the L PS-induced synthesis of lL-1beta mRNA and IL-1beta protein. After a pr eincubation time of 1 h, 100 U/ml of IFN-gamma increased the 1,PS-indu ced IL-Ibeta production by about 20-40%. When human monocytes were pre incubated for 1 h with IFN-gamma (100 U/ml) prior to the addition of d examethasone (10(-6) M) and prior to the stimulation with LPS, the dex amethasone-mediated inhibition of IL-1beta mRNA and IL-1beta protein s ynthesis was totally neutralized by IFN-gamma. In addition, IFN-gamma totally overcame the negative effect of IL-4 (100 pM) on lL-1beta prot ein synthesis. A preincubation period of at least 1 h with IFN-gamma w as necessary for the neutralization of the dexamethasone effect. If IF N-gamma was given at the same time or after dexamethasone, only a weak effect was found. The presence of IFN-gamma during the stimulation pe riod with LPS was not necessary for the potentiating effect on IL-1bet a synthesis, as shown by pulse-treating the monocytes for 1 to 4 h, pr ior to the stimulation with LPS. In contrast, the neutralization of th e dexamethasone-mediated inhibition of IL-1beta synthesis was strictly dependent on the presence of IFN-gamma during the stimulation period with LPS. The potentiation of LPS-induced IL-1beta mRNA expression by IFN-gamma was not influenced when protein synthesis was blocked by the addition of cycloheximide (5 mug/ml). In contrast, in the absence of protein synthesis, IFN-gamma neither neutralized the negative effect o f dexamethasone nor the effect of IL-4 on IL-1beta mRNA synthesis, ind icating that newly synthesized proteins might be involved in the neutr alization of the dexamethasone- and IL-4-mediated inhibition of IL-1be ta synthesis by IFN-gamma. Our results suggest that the therapeutic ef fect of steroids in the treatment of chronic inflammatory joint diseas es might be drastically reduced by the presence of additional cytokine s, such as IFN-gamma, which has been detected in the synovial tissue a nd the synovial fluid of rheumatoid arthritis patients.