Mesangial cell Fas ligand: upregulation in human lupus nephritis and NF-κB-mediated expression in cultured human mesangial cells
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We investigated the renal expression and localization 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).
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.
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.
- Mesangial cell Fas ligand: upregulation in human lupus nephritis and NF-κB-mediated expression in cultured human mesangial cells
Journal of Clinical and Experimental Nephrology
Volume 8, Issue 3 , pp 196-205
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- Matrix metalloproteinase
- Nuclear factor κB
- Soluble Fas ligand
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- Author Affiliations
- A1. Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan