Cytokines in human renal interstitial fibrosis. II. Intrinsic interleukin (IL)-1 synthesis and IL-1-dependent production of IL-6 and IL-8 by cultured kidney fibroblasts.

We compared cytokine production from transformed human fibroblast cell lines derived from either a kidney with interstitial fibrosis or a normal 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 fibroblasts was dependent on the intrinsic release of IL-1, since blocking IL-1 receptors with IL-1 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 and skin fibroblasts stimulated by picomolar concentrations of exogenous IL-1 or TNF-alpha produced large amounts of IL-6 and IL-8, whereas nanomolar concentrations of basic fibroblast growth factor did not. Fibrosis-derived cells expressed less high affinity IL-1 receptors (600 receptors/cell; KD = 0.6 pM) compared to normal renal fibroblasts (1000 receptors/cell). However, fibrosis-derived renal fibroblasts produce three- to fourfold more IL-8 and IL-6 in response to picomolar concentrations 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 receptors, we speculate that post-receptor responsiveness to either endogenous or exogenous IL-1 is greater in fibrosis-derived renal fibroblasts than in cells from normal kidneys.