TISSUE-SPECIFIC REGULATION OF IL-6 PRODUCTION BY IL-4 - DIFFERENTIAL-EFFECTS OF IL-4 ON NUCLEAR FACTOR-KAPPA-B ACTIVITY IN MONOCYTES AND FIBROBLASTS

IL-4 inhibits production of certain proinflammatory cytokines, includi ng IL-1beta, TNF-alpha, and IL-6, by activated monocytes. Although mon ocytes are a major source of IL-6, other cell types such as fibroblast s and endothelial cells can also express this cytokine. To determine w hether IL-4 inhibits IL-6 expression in non-hemopoietic cells, we inve stigated the effects of IL-4 on IL-6 production in both primary human fibroblasts and fibroblast lines. Rheumatoid synovial fibroblasts were evaluated in these studies because, like monocytes, they produce high levels of IL-6 when stimulated with IL-1. Although peripheral blood m onocytes did not constitutively express IL-6 mRNA or protein, stimulat ion with IL-1 or LPS induced de novo IL-6 expression in these cells. I n contrast, synovial fibroblasts displayed a significant basal level o f IL-6 production, which was markedly increased after stimulation with IL-1. IL-4 suppressed IL-6 expression in monocytes, but did not inhib it IL-6 production in synovial fibroblasts. The inability of IL-4 to s uppress IL-6 synthesis in rheumatoid synovial fibroblasts was not caus ed by a lack of IL-4R and was not unique to these cells because IL-4 a lso failed to inhibit IL-6 production in normal fibroblast lines deriv ed from other tissues. Inhibition of IL-6 production by IL-4 in monocy tes was associated with decreased nuclear NF-kappaB levels. However, I L-4 does not globally suppress the activity of all DNA-binding protein s because IL-4 treatment did not reduce the levels of NF-IL-6 or NF-IL -1betaB in the same cells. Because NF-kappaB activation is required fo r transcription of many cytokine genes, including IL-6, the ability of IL-4 to suppress NF-kappaB activity in monocytes suggests a potential mechanism by which this molecule may inhibit the expression of multip le cytokines.