Inhibition of tumor necrosis factor alpha-induced prostaglandin E2 production by the antiinflammatory cytokines interleukin-4, interleukin-10, and interleukin-13 in osteoarthritic synovial fibroblasts: distinct targeting in the signaling pathways

Arthritis Rheum. 1999 Apr;42(4):710-8. doi: 10.1002/1529-0131(199904)42:4<710::AID-ANR14>3.0.CO;2-4.

Abstract

Objective: To investigate the effects of the antiinflammatory cytokines interleukin-4 (IL-4), IL-10, and IL-13 on tumor necrosis factor alpha (TNFalpha)-induced prostaglandin E2 (PGE2) release in the cellular signaling cascade on human osteoarthritis (OA) synovial fibroblasts.

Methods: Human OA synovial fibroblasts were cultured to explore the impact of IL-4, IL-10, and IL-13 on TNFalpha binding to TNF receptors (TNFR), soluble TNFR (sTNFR), cytoplasmic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX-2) production, and on the binding activity of the transcription factors nuclear factor kappaB (NF-kappaB), CCAAT-enhancer binding protein (C/EBP), activator protein 2 (AP-2), and cyclic AMP response element-binding protein (CREB).

Results: IL-4, IL-10, and IL-13 at 5 ng/ml dramatically reduced TNFalpha-induced PGE2 release by approximately 90% (P < 0.0001). IL-4 up-regulated the level of TNFalpha-induced TNFR by 47% (P < 0.06), while IL-10 down-regulated it by 71% (P < 0.02); IL-13 had no effect. Although statistical significance was not reached, all 3 cytokines up-regulated the basal level of sTNFR-55. IL-4 and IL-10, while not altering the basal level of sTNFR-75, significantly increased the TNFalpha-stimulated release of sTNFR-75. IL-4, IL-10, and IL-13 reduced the TNFalpha-induced COX-2 level, and IL-4 and IL-10 reduced the cPLA2 level. IL-4 had no effect on TNFalpha up-regulation of NF-kappaB, and a slight decrease was noted with IL-10 and IL-13 at the highest concentration used (5 ng/ml). IL-4 and IL-13 decreased the TNFa-induced C/EBP accumulation in a dose-dependent manner, while IL-10 up-regulated its basal level. AP-2 and CREB were not induced by TNFalpha.

Conclusion: The results indicate that these antiinflammatory cytokines reversed the TNFalpha-induced release of PGE2 by OA synovial fibroblasts, by acting at various levels of the TNFa-dependent signaling cascade. These data shed new light on the mechanisms by which these cytokines reduce inflammatory processes.

MeSH terms

  • Blotting, Northern
  • CCAAT-Enhancer-Binding Proteins
  • Cyclic AMP / immunology
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / immunology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclooxygenase 2
  • Cytoplasm / enzymology
  • Cytoplasm / immunology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Dinoprostone / immunology
  • Dinoprostone / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Enzymologic / immunology
  • Humans
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism
  • Interleukin-13 / immunology
  • Interleukin-13 / metabolism
  • Interleukin-4 / immunology
  • Interleukin-4 / metabolism
  • Interleukins / immunology
  • Interleukins / metabolism*
  • Isoenzymes / genetics
  • Isoenzymes / immunology
  • Isoenzymes / metabolism
  • Membrane Proteins
  • Middle Aged
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology
  • Nuclear Proteins / metabolism
  • Osteoarthritis / immunology
  • Osteoarthritis / metabolism*
  • Phospholipases A / immunology
  • Phospholipases A / metabolism
  • Phospholipases A2
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / immunology
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • RNA, Messenger / analysis
  • Signal Transduction / immunology
  • Synovial Membrane / cytology
  • Synovial Membrane / enzymology
  • Synovial Membrane / immunology
  • Transcription Factor AP-2
  • Transcription Factors / genetics
  • Transcription Factors / immunology
  • Transcription Factors / metabolism
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Interleukin-13
  • Interleukins
  • Isoenzymes
  • Membrane Proteins
  • NF-kappa B
  • Nuclear Proteins
  • RNA, Messenger
  • Transcription Factor AP-2
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-4
  • Cyclic AMP
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Phospholipases A
  • Phospholipases A2
  • Dinoprostone