Cartilage and joint inflammation. Regulation of IL-8 expression by human articular chondrocytes.
Injury to cartilage is a recognized sequela of neutrophil activation in arthritic joints. This study examined the possibility that chondrocytes may play a direct role in intraarticular neutrophil activation. We demonstrate that IL-1 beta-stimulated primary and subcultured human articular chondrocytes, express the gene for the potent neutrophil chemotactic and activating cytokine, IL-8. Expression of IL-8 mRNA is also inducible by TNF-alpha and LPS and, to a lesser degree, by the chondrocyte growth factor, transforming growth factor-beta, but not by platelet-derived growth factor, acidic and basic fibroblast growth factor, or epidermal growth factor. Analysis of IL-1 beta-stimulated cartilage organ cultures by in situ hybridization demonstrates that chondrocytes in all zones of cartilage are rapidly induced to express the IL-8 gene in high copy number. Metabolically labeled IL-1 beta-stimulated chondrocytes synthesize IL-8 de novo, which comigrates on SDS-PAGE with IL-8 produced by synovial fibroblasts. Furthermore, the conditioned media of IL-1 beta-stimulated chondrocytes and cartilage organ cultures contain neutrophil chemotactic activity which is completely neutralized by a specific antibody to IL-8, establishing that a bioactive form of IL-8 is the major secreted neutrophil chemotactic factor. By using a specific RIA, we demonstrate that not only IL-1 beta, but also TNF-alpha and LPS can induce abundant IL-8 secretion from chondrocytes. In conclusion, articular chondrocytes are readily inducible to express the IL-8 gene and secrete biologically active IL-8 which can promote neutrophil-mediated inflammation and cartilage destruction.
Lotz
M
M
Sam and Rose Stein Institute for Research on Aging, Department of Medicine, University of California, San Diego, La Jolla 92093.
Terkeltaub
R
R
Villiger
P M
PM
D001168:Arthritis / Q000209:etiology*; D001483:Base Sequence; D002358:Cartilage, Articular / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics*; D008070:Lipopolysaccharides; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000502:physiology; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha