CYTOKINES IN HUMAN RENAL INTERSTITIAL FIBROSIS .2. INTRINSIC INTERLEUKIN (TL)-1 SYNTHESIS AND IL-1-DEPENDENT PRODUCTION OF IL-6 AND IL-8 BYCULTURED KIDNEY FIBROBLASTS

We compared cytokine production from transformed human fibroblast cell lines derived from either a kidney with interstitial fibrosis or a no rmal kidney to that from primary human foreskin fibroblasts. Fibrosis- derived as well as normal renal fibroblasts, but not skin fibroblasts, spontaneously produced the chemokine, IL-8, and the growth promoting cytokine, IL-6. Spontaneous IL-8 and IL-6 synthesis by renal fibroblas ts was dependent on the intrinsic release of IL-1, since blocking IL-I receptors with LL-I receptor antagonist (IL-1Ra) partially inhibited the constitutive production of these cytokines. Both kidney cell lines had detectable mRNA and protein for IL-1 alpha and IL-1 beta. Renal a nd skin fibroblasts stimulated by picomolar concentrations of exogenou s IL-1 or TNF-alpha produced large amounts of IL-6 and IL-8, whereas n anomolar concentrations of basic fibroblast growth factor did not. Fib rosis-derived cells expressed less high affinity IL-1 receptors (600 r eceptors/cell; K-D = 0.6 pM) compared to normal renal fibroblasts (100 0 receptors/cell). However, fibrosis-derived renal fibroblasts produce three- to fourfold more IL-8 and IL-6 in response to picomolar concen trations of IL-1 beta compared to cells derived from a normal kidney. As this enhanced production is not due to increased numbers of IL-1 re ceptors, we speculate that post-receptor responsiveness to either endo genous or exogenous IL-1 is greater in fibrosis-derived renal fibrobla sts than in cells from normal kidneys.