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- Title
Mesangial cell Fas ligand: upregulation in human lupus nephritis and NF-?B-mediated expression in cultured human mesangial cells.
- Authors
Tsukinoki, Tomoko; Sugiyama, Hitoshi; Sunami, Reiko; Kobayashi, Mizuho; Onoda, Tetsuya; Maeshima, Yohei; Yamasaki, Yasushi; Makino, Hirofumi
- Abstract
Background. Fas ligand (FasL) is a well-known death factor; however, the role of FasL in the regulation of human glomerulonephritis remains unclear. Methods. We investigated the renal expression and localiza- tion of FasL in various forms of human glomerulonephritis by immunohistochemistry, utilizing confocal laser scanning microscopy. We further evaluated cytokine-induced FasL expression via nuclear factor (NF)κB in cultured human mesangial cells (HMC). The level of soluble FasL was measured by a specific enzyme-linked immunosorbent assay (ELISA). Results. The frequency of glomerular FasL-positive cases was higher in lupus nephritis (37.9%) as compared with other forms of glomerulonephritis (8.7%). The glomerular FasL score in proliferative lupus nephritis was significantly higher than that in nonproliferative forms. Patients with a high apoptosis score, severe microhematuria, proteinuria, or decreased renal function had a high FasL score. Double immunolabelling demonstrated that the most prevalent phenotypes of FasL-positive cells were mesangial cells. In cultured HMC, interleukin (IL)1β, lipopolysaccharide (LPS), or γ interferon (IFN) upregulated membrane-bound FasL. IL1β significantly, and LPS or γIFN weakly activated NFκB, but none of these agents activated NFκB/Rel-related nuclear factor of activated T cells (NFATc) or IFN regulatory factor-1. IL1β-mediated NFκB was completely inhibited in the presence of lactacystin, a potent inhibitor of NFκB. Lactacystin-mediated inhibition of NFκB reduced FasL protein levels. Matrix metalloproteinase (MMP)-7, but not other MMPs (1, 2, 3, 8, or 9), significantly sensitized HMC to release soluble FasL after IL1β stimulation. Conclusions. The results suggest that: (1) upregulation of mesangial FasL may contribute to the glomerular inflammation in proliferative lupus nephritis in vivo; (2) proinflammatory cytokines, in particular IL1β, produced in nephritis can upregulate FasL via the transcription factor NFκB in HMC; and (3) MMP-7-mediated release of soluble FasL could control the mesangial inflammation.
- Subjects
APOPTOSIS; INTERLEUKIN-1; LUPUS nephritis; METALLOPROTEINASES; NF-kappa B; GLOMERULONEPHRITIS; KIDNEY glomerulus diseases; ENZYME-linked immunosorbent assay
- Publication
Clinical & Experimental Nephrology, 2004, Vol 8, Issue 3, p196
- ISSN
1342-1751
- Publication type
Article
- DOI
10.1007/s10157-004-0301-3