TISSUE SPECIFIC REGULATION OF CYTOKINE PRODUCTION BY IL-4

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IL-4 inhibits production of certain proinflammatory cytokines, including IL-1a, TNF-a and IL-6, by activated monocytes. Although monocytes are a major source of IL-6, other cell types such as fibroblasts and endothelial cells, can also express this cytokine. To determine whether IL-4 inhibits cytokine expression in non-hematopoietic cells, we investigated 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 monocytes did not constitutively express IL-6 mRNA or protein, stimulation with IL-1 or LPS induced de novo IL-6 expression in these cells. In contrast, synovial fibroblasts displayed a significant basal level of IL-6 production which was markedly increased following stimulation with IL-1. IL-4 suppressed IL-6 expression in monocytes, but did not inhibit IL-6 production in synovial fibroblasts. The inability of IL-4 to suppress IL-6 synthesis in rheumatoid synovial fibroblasts was not secondary to an absence of IL-4 receptors, and was not unique to these cells because IL-4 also failed to inhibit IL-6 production in normal fibroblast lines derived from other tissues. Inhibition of IL-6 production by IL-4 in monocytes correlated with suppression of nuclear factor-kappa B (NF-kB) activity. However, IL-4 did not decrease the levels of other nuclear factors, including NF-IL6, NF-IL-1B and AP-1 in either monocytes or fibroblasts. Because NF-kB activation is required for transcription of many proinflammatory cytokine genes, including IL-6, the ability of IL-4 to suppress NF-kB activity in monocytes suggests a potential mechanism by which this molecule may inhibit the expression of multiple cytokines.