EXPRESSION OF THE CYTOKINE RANTES IN HUMAN RHEUMATOID SYNOVIAL FIBROBLASTS - DIFFERENTIAL REGULATION OF RANTES AND INTERLEUKIN-8 GENES BY INFLAMMATORY CYTOKINES

A chronic inflammatory disease may be characterized by an accumulation of activated leukocytes at the site of inflammation. Since the chemokine RANTES may play an active role in recruiting leukocytes into inflammatory sites, we investigated the ability of cultured human synovial fibroblasts isolated from patients suffering from rheumatoid arthritis to produce this chemokine and compared its regulation to that of the closely related chemokine gene, interleukin-8 (IL-8). In unstimulated synovial fibroblasts, the expression of mRNA for both chemokines was undetectable, but was increased in both a time- and dose-dependent manner upon stimulation with the monokines tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta). Preincubation of the cells with cycloheximide ''superinduced'' the level of IL-8 mRNA stimulated by TNFalpha and IL-1beta and RANTES mRNA stimulated by IL-1beta, but decreased the expression of RANTES mRNA in response to TNFalpha. In addition, differential regulation of these genes was noted when synovial fibroblasts were stimulated with a combination of cytokines. IL-4 down-regulated and IFNgamma enhanced the TNFalpha- and IL-1beta-induced increase in RANTES mRNA, whereas the induction of IL-8 mRNA by TNFalpha or IL-1beta was inhibited by IFNgamma and augmented by IL-4. Moreover, a combination of TNFalpha and IL-1beta synergistically induced IL-8 mRNA expression, whereas under the same conditions, the level of expression of RANTES mRNA was less than that induced by TNFalpha alone. These observations were also reflected at the level of chemokine secretion. These studies demonstrate that by expressing the chemokines RANTES and IL-8, synovial fibroblasts may participate in the ongoing inflammatory process in rheumatoid arthritis. In addition, the observation that these chemokine genes are differentially regulated, depending upon the presence of different cytokines, indicates that the type of cellular infiltrate and the progress of the inflammatory disease is likely to depend on the relative levels of stimulatory and inhibitory cytokines.