| Summary: | 博士 === 國立臺灣大學 === 免疫學研究所 === 107 === We generated a human dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN) transgenic mouse in which renal tubular epithelial cells expressed DC-SIGN. Transgenic mice were infected with Candida albicans intravenously to study how DC-SIGN expression affects the pathogenesis of systemic candidiasis. We discovered that while C. albicans infection induced renal fibrosis in both transgenic and littermate control mice, the transgenic mice had significantly less Acta2, Col1a2, Col3a1 and Col4a1 transcripts compared to the controls. KIM-1, an emerging biomarker for kidney injury, along with Tnf, Il6 and Tgfb1 transcripts were lower in infected transgenic mice yet that of Il10 remained comparable to controls. While renal CD45+ infiltrating cells were the source of Tnf, Il6 and Il10, LTL+ renal proximal tubular epithelial cells were TGF-β1 producers in both infected transgenic and littermate controls. In vitro study showed that DC-SIGN-expressing primary tubular epithelial cells produced less TGF-β1 upon C. albicans infection. Employing anti-TGF-β neutralizing antibody we demonstrated that production of TGF-β was key to C. albicans-induced renal fibrosis and injury. Infection of transgenic mice induced in the kidney a marked increase of phosphorylated Raf-1 and p38. However, ERK1/2 and JNK phosphorylation was more pronounced in infected-littermate controls. Interestingly, treating infected transgenic mice with Raf-1 inhibitor increased the levels of Tgfb1, Kim1 and Acta2 transcripts. These results indicate that DC-SIGN signaling, through activating Raf-1 and p38 and suppressing JNK and ERK1/2 phosphorylation, reduces TGF-β1 production and C. albicans-induced renal fibrosis. Our study reveals for the first time the effect of DC-SIGN expression on C. albicans-induced renal fibrosis.
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