Implication of interleukin 18 in production of matrix metalloproteinases in articular chondrocytes in arthritis: direct effect on chondrocytes may not be pivotal

• Published in: Annals of the rheumatic diseases Vol. 64; no. 5; pp. 735 - 742
• Main Authors: Dai, S-M, Shan, Z-Z, Nishioka, K, Yudoh, K
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and European League Against Rheumatism 01.05.2005; BMJ; Elsevier Limited
• Subjects: ADAM Proteins; ADAMTS5 Protein; Adult; Aged; Aged, 80 and over; Arthritis; Arthritis - enzymology; Arthritis - metabolism; Arthritis - pathology; Arthritis, Rheumatoid - enzymology; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; articular cartilage; Bacterial arthritis and osteitis; Bacterial diseases; Biological and medical sciences; c-Jun N-terminal kinase; Cartilage, Articular - enzymology; Cartilage, Articular - pathology; Cells, Cultured; chondrocytes; Chondrocytes - drug effects; Chondrocytes - enzymology; Chondrocytes - metabolism; Collagen; Cytokines; Deoxyribonucleic acid; Diseases of the osteoarticular system; DMEM; DNA; Dulbecco’s modified Eagle’s medium; ELISA; enzyme linked immunosorbent assay; Enzyme-Linked Immunosorbent Assay - methods; Extended Report; Extracellular matrix; GAPDH; Gene Expression Regulation - drug effects; glyceraldehyde-3-phosphate dehydrogenase; Human bacterial diseases; Humans; IL18R; Infectious diseases; interleukin; interleukin 18; interleukin 18 receptor; Interleukin-18 - biosynthesis; Interleukin-18 - genetics; Interleukin-18 - pharmacology; JNK; Joint surgery; Kinases; MAPK; matrix metalloproteinase; Matrix Metalloproteinases - biosynthesis; Medical sciences; MEK; Metalloendopeptidases - biosynthesis; Metalloendopeptidases - genetics; metalloproteinases; Middle Aged; Miscellaneous. Osteoarticular involvement in other diseases; mitogen activated protein kinase; mitogen activated protein kinase/extracellular signal regulated kinase kinase; MMP; NF-κB; nuclear factor κB; osteoarthritis; Osteoarthritis - enzymology; Osteoarthritis - metabolism; Osteoarthritis - pathology; PGE2; prostaglandin E2; Proteins; Reverse Transcriptase Polymerase Chain Reaction - methods; reverse transcriptase-polymerase chain reaction; rheumatoid arthritis; RNA, Messenger - genetics; Rodents; RT-PCR; Signal Transduction; Studies; TIMPs; Tissue Inhibitor of Metalloproteinase-1 - biosynthesis; tissue inhibitors of metalloproteinases; TNFα; tumour necrosis factor α; Japan; Arthritis; Chondrocyte; Diseases of the osteoarticular system; Production; Interleukin 18
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/ard.2004.026088

Objective: To clarify the effect of interleukin (IL) 18 on cartilage degeneration by studying the profile of IL18 receptor (IL18R) on chondrocytes and the direct effect of IL18 on production of matrix metalloproteinases (MMPs), aggrecanases, and tissue inhibitors of metalloproteinases (TIMPs) in articular chondrocytes. Methods: Monolayer cultured human articular chondrocytes were isolated from non-arthritic subjects and patients with rheumatoid arthritis or osteoarthritis. Gene expression of IL18, IL18Rα, IL18Rβ, MMPs, and aggrecanases was detected by RT-PCR. Protein levels of IL18Rα were analysed by flow cytometry. Protein levels of IL18, MMPs, and TIMPs were measured by ELISA. Aggrecanase-2 mRNA expression was quantitatively analysed by real time RT-PCR. Protein levels of signalling molecules were assayed by western blotting. Results: IL18 mRNA was constitutively expressed in chondrocytes, and was enhanced by IL1β stimulation. Flow cytometric analysis showed that IL1β, tumour necrosis factor α, and IL18 up regulated IL18Rα expression levels. The level of IL18Rβ mRNA was much lower than that of IL18Rα, and was slightly up regulated by IL1β. In chondrocytes responding to IL18, IL18 (1–100 ng/ml) slightly increased the production of MMP-1, MMP-3, and MMP-13, which was blocked by NF-κB inhibitor and p38 mitogen activated protein kinase inhibitor. IL18 up regulated mRNA expression of aggrecanase-2, but not aggrecanase-1. IL18 also slightly stimulated TIMP-1 production?through extracellular signal regulated kinase activation. Conclusion: IL18 induces production of MMPs from chondrocytes in inflammatory arthritis. Although the direct effect of IL18 on chondrocytes may not be pivotal for the induction of cartilage degeneration, IL18 seems to play some part in the degradation of articular cartilage in arthritis.