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Transgenic Mice
* Department of Orthopedic Surgery, Keio University, Tokyo, Japan;
Department of Orthopedic Surgery, Fujita Health University, Aichi, Japan;
Department of Orthopedic Surgery, National Defense Medical College, Saitama, Japan; and
Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan
IL-1 molecules are encoded by two distinct genes, IL-1
and IL-1
. Both isoforms possess essentially identical activities and potencies, whereas IL-1, in contrast to IL-1, 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-1 (hIL-1) 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-1 amino acid sequence, Tg mice may overproduce MA-IL-1 as well as soluble IL-1. 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-1 activity or concentration of serum hIL-1. Moreover, when the Tg1706 line was compared with the Tg101 line, which selectively overexpresses the 17-kDa mature hIL-1, 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.
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