EFFECTS OF IFN-GAMMA AND IL-4 ON IL-1 PRODUCTION BY HUMAN MONOCYTES

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In this project we investigated the effects of two distinct T cell-derived lymphokines, IFN-gamma and IL-4, on the ability of human monocytes to produce IL-1. IL-4 inhibits IL-1 production by highly purified normal human monocytes. We have found that Inhibition Is maximal or near maximal with IL-4 concentrations as low as ng/ml and most pronounced when IL-4 is added to monocyte cultures prior to or simultaneous with an IL-1 inducing stimulus such as LPS. Northern blot analyses revealed that IL-4 not only dramatically, reduced the steady-state message levels for IL-1 beta but also those of TNF alpha and IL-6. The inhibitory effect was not stimulus-specific because IL-4 suppressed IL-1 production Induced by three distinct monocyte activation stimuli: LPS, PMA and Staphylococcus aureus Cowan (SAC). Furthermore, monocytes expressed a relatively small number of high affinity IL-4 receptors (l50-300R per cell; Kd - 32 pill) indicating that relatively few receptors are necessary to generate the inhibitory, effect. Although both IFN-gamma and IL-4 upregulated MHC class II antigen (HLA-DR) expression by monocytes, they exhibited opposite effects on IL-1 production: IFN-gamma significantly enhanced IL-1 production induced by submaximal concentrations of LPS; whereas, IL-4 suppressed IL-1 production. Moreover, IL-4 largely neutralized the potentiating effect of IFN-gamma suggesting that IL-4 may be an effective antagonist of certain IFN-gamma-- inducible effects. These findings demonstrate that the relative levels of IFN-gamma and IL-4 may profoundly influence the expression of IL-1, a property that may be important in the control of monocyte/macrophage activation at specific tissue sites. These findings also suggest that IL-4 might have clinical utility as an antiinflammatory agent in the treatment of diseases such as rheumatoid arthritis where overexpression of the monokines IL-1, TNF alpha and IL-6 has been observed.