Membrane-Associated IL-1 Contributes to Chronic Synovitis and Cartilage Destruction in Human IL-1α Transgenic Mice

Yasuo Niki, Harumoto Yamada, Toshiyuki Kikuchi, Yoshiaki Toyama, Hideo Matsumoto, Kyosuke Fujikawa, Norihiro Tada

Research output: Contribution to journalArticle

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Abstract

IL-1 molecules are encoded by two distinct genes, IL-1α and IL-1β. Both isoforms possess essentially identical activities and potencies, whereas IL-1α, in contrast to IL-1β, is known to act as a membrane-associated IL-1 (MA-IL-1) and plays an important role in a variety of inflammatory situations. The transgenic (Tg) mouse line (Tg1706), which was generated in our laboratory, overexpresses human IL-1α (hIL-1α) and exhibits a severe arthritic phenotype characterized by autonomous synovial proliferation with subsequent cartilage destruction. Because the transgene encoded Lys64 to Ala271 of the hIL-1α amino acid sequence, Tg mice may overproduce MA-IL-1 as well as soluble IL-1α. The present study investigated whether MA-IL-1 contributes to synovial proliferation and cartilage destruction in the development of arthritis. Flow cytometric analysis revealed that both macrophage-like and fibroblast-like synoviocytes constitutively produce MA-IL-1. D10 cell proliferation assay revealed MA-IL-1 bioactivity of paraformaldehyde-fixed synoviocytes and the further induction of endogenous mouse MA-IL-1 via autocrine mechanisms. MA-IL-1 expressed on synoviocytes triggered synoviocyte self-proliferation through cell-to-cell (i.e., juxtacrine) interactions and also promoted proteoglycan release from the cartilage matrix in chondrocyte monolayer culture. Interestingly, the severity of arthritis was significantly correlated with MA-IL-1 activity rather than with soluble IL-1α activity or concentration of serum hIL-1α. Moreover, when the Tg1706 line was compared with the Tg101 line, which selectively overexpresses the 17-kDa mature hIL-1α, the severity of arthritis was significantly higher in the Tg1706 line than in the Tg101 line. These results suggest that MA-IL-1 contributes to synoviocyte self-proliferation and subsequent cartilage destruction in inflammatory joint disease such as rheumatoid arthritis.

Original languageEnglish
Pages (from-to)577-584
Number of pages8
JournalJournal of Immunology
Volume172
Issue number1
Publication statusPublished - 01-01-2004

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Synovitis
Interleukin-1
Transgenic Mice
Cartilage
Membranes
Arthritis
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

Niki, Y., Yamada, H., Kikuchi, T., Toyama, Y., Matsumoto, H., Fujikawa, K., & Tada, N. (2004). Membrane-Associated IL-1 Contributes to Chronic Synovitis and Cartilage Destruction in Human IL-1α Transgenic Mice. Journal of Immunology, 172(1), 577-584.
Niki, Yasuo ; Yamada, Harumoto ; Kikuchi, Toshiyuki ; Toyama, Yoshiaki ; Matsumoto, Hideo ; Fujikawa, Kyosuke ; Tada, Norihiro. / Membrane-Associated IL-1 Contributes to Chronic Synovitis and Cartilage Destruction in Human IL-1α Transgenic Mice. In: Journal of Immunology. 2004 ; Vol. 172, No. 1. pp. 577-584.
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Niki, Y, Yamada, H, Kikuchi, T, Toyama, Y, Matsumoto, H, Fujikawa, K & Tada, N 2004, 'Membrane-Associated IL-1 Contributes to Chronic Synovitis and Cartilage Destruction in Human IL-1α Transgenic Mice', Journal of Immunology, vol. 172, no. 1, pp. 577-584.

Membrane-Associated IL-1 Contributes to Chronic Synovitis and Cartilage Destruction in Human IL-1α Transgenic Mice. / Niki, Yasuo; Yamada, Harumoto; Kikuchi, Toshiyuki; Toyama, Yoshiaki; Matsumoto, Hideo; Fujikawa, Kyosuke; Tada, Norihiro.

In: Journal of Immunology, Vol. 172, No. 1, 01.01.2004, p. 577-584.

Research output: Contribution to journalArticle

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AU - Niki, Yasuo

AU - Yamada, Harumoto

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AU - Tada, Norihiro

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