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.
Lonnemann
G
G
Department of Medicine, New England Medical Center Hospital, Boston, Massachusetts, USA.
Engler-Blum
G
G
Müller
G A
GA
Koch
K M
KM
Dinarello
C A
CA
D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D011863:Radioimmunoassay; D012795:Sialoglycoproteins / Q000494:pharmacology*; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha