Interleukin-1β stimulates human renal fibroblast proliferation and matrix protein production by means of a transforming growth factor-β-dependent mechanism

• DOI: 10.1067/mlc.2002.128468
• Publication Date: 2002-12-03T12:41:52Z
• Authors: David A. Vesey; Catherine Cheung; Leila Cuttle; Zoltan Endre; Glenda Gobe; David W. Johnson
• Keywords: Male; Antibodies/immunology/pharmacology; Pathogenesis; Collagen-synthesis; Kidney Cortex/cytology/*drug effects/metabolism; 0302 clinical medicine; Nitric-oxide; Transforming Growth Factor beta; Enzyme Inhibitors; Extracellular Matrix Proteins/*drug effects/metabolism; Cells, Cultured; Enzyme Inhibitors/pharmacology; Extracellular Matrix Proteins; Cultured; Research & Experimental; Epithelial-cells; Tetradecanoylphorbol Acetate/pharmacology; 3. Good health; Medical Laboratory Technology; Mesangial Cells; Medicine; Tetradecanoylphorbol Acetate; Female; Kinase-c; Drug; Interleukin-1/*pharmacology; Fibronectins/metabolism; Proximal Tubule Cells; Tumor-necrosis-factor; DNA Replication; Kidney Cortex; 110312 Nephrology and Urology; DNA/biosynthesis; Cells; 610; Collagen Type I/metabolism; General & Internal; Nitric Oxide; Fibroblasts/cytology/*drug effects/metabolism; Antibodies; Collagen Type I; Dose-Response Relationship; 03 medical and health sciences; C1; Humans; Dose-Response Relationship, Drug; *Transforming Growth Factor beta/immunology/metabolism; DNA; Fibroblasts; DNA Replication/drug effects; Fibronectins; 730118 Organs; diseases and abnormal conditions not elsewhere classified; Nitric Oxide/metabolism; Angiotensin-ii; Factor-alpha; Interleukin-1

One of the hallmarks of progressive renal disease is the development of tubulointerstitial fibrosis. This is frequently preceded by macrophage infiltration, raising the possibility that macrophages relay fibrogenic signals to resident tubulointerstitial cells. The aim of this study was to investigate the potentially fibrogenic role of interleukin-1beta (IL-1beta), a macrophage-derived inflammatory cytokine, on cortical fibroblasts (CFs). Primary cultures of human renal CFs were established and incubated for 24 hours in the presence or absence of IL-1beta. We found that IL-1beta significantly stimulated DNA synthesis (356.7% +/- 39% of control, P <.003), fibronectin secretion (261.8 +/- 11% of control, P <.005), collagen type 1 production, (release of procollagen type 1 C-terminal-peptide, 152.4% +/- 26% of control, P <.005), transforming growth factor-beta (TGF-beta) secretion (211% +/- 37% of control, P <.01), and nitric oxide (NO) production (342.8% +/- 69% of control, P <.002). TGF-beta (1 ng/mL) and the phorbol ester phorbol 12-myristate 13-acetate (PMA, 25 nmol/L) produced fibrogenic effects similar to those of IL-1beta. Neither a NO synthase inhibitor (N(G)-methyl-l-arginine, 1 mmol/L) nor a protein kinase C (PKC) inhibitor (bis-indolylmaleimide 1, 1 micromol/L) altered the enhanced level of fibronectin secretion or DNA synthesis seen in response to IL-1beta treatment. However, addition of a TGF-beta-neutralizing antibody significantly reduced IL-1beta-induced fibronectin secretion (IL-1beta + IgG, 262% +/- 72% vs IL-1beta + alphaTGF-beta 156% +/- 14%, P <.02), collagen type 1 production (IL-1beta + IgG, 176% +/- 28% vs IL-1beta + alphaTGF-beta, 120% +/- 14%, P <.005) and abrogated IL-1beta-induced DNA synthesis (245% +/- 49% vs 105% +/- 21%, P <.005). IL-1beta significantly stimulated CF DNA synthesis and production of fibronectin, collagen type 1, TGFbeta, and NO. The fibrogenic and proliferative action of IL-1beta on CF appears not to involve activation of PKC or production of NO but is at least partly TGFbeta-dependent.