IL-1αトランスジェニックマウスにおける関節破壊 : 滑膜増殖, 軟骨破壊における膜型IL-1の重要性(<特集>外科領域)

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Transgenic mice overexpressing human IL-1α(hIL-1α)exhibit chronic polyarthritis characterized by formation of hyperplastic synovial tissue(pannus), and marked infiltration of neutrophils.Herein, we presented that transgene-derived hIL-1α acted as both soluble form and membrane-associated form and further induced endogenous membrane-associated IL-1(MA-IL-1).MA-IL-1 activity of paraformaldehyde(PFA)-fixed synoviocytes could be confirmed by T cell proliferation assay using IL-1-sensitve mouse CD4+cell line, D10.G4.1.During the assay, incubation with anti-human or anti-mouse IL-1α antibody resulted in the remarkable neutralization of the MA-IL-1 activity, suggesting, that both human and mouse MA-IL-1 existed on the surface of synoviocytes.This indicated that transgene-derived MA-IL-1 induces endogenous MA-IL-1 through an autocrine mechanism.It is noteworthy that synoviocytes expressing MA-IL-1 enhanced their own proliferation.In this situation, direct cell to cell contact was indispensable to promote such enhanced proliferation since the proliferation was markedly abrogated when overlaid synoviocytes were separated from PFA-fixed synoviocytes through cell culture insert.Furthermore, MA-IL-1 could stimulate proteoglycan release from chondrocytes in monolayer culture.In conclusion, transgenederived IL-1α was partly expressed as MA-IL-1 and MA-IL-1-stimulated synoviocytes may trigger their own proliferation and induce degradation of cartilage adjacent to the synovial pannus through cell to cell interaction, i.e.juxtacrine machanism during the course of arthritis.
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IL-1αトランスジェニックマウスにおける関節破壊 : 滑膜増殖, 軟骨破壊における膜型IL-1の重要性(<特集>外科領域)

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