CD14 Contributes to Increased Inflammation and Fibrogenesis in Lupus Nephritis

Abstract

BACKGROUND: CD14 is a GPI-anchored membrane protein that serves as a pattern recognition receptor in the clinical setting of sepsis. CD14 transfers lipopolysaccharide (LPS) from the acute phase protein LPS-binding protein (LBP) to TLR-4/MD-2 complex, to initiate signal transduction and cytokines release. Serum CD14 level is increased in SLE patients, but little is known about its clinical significance or pathogenic role in lupus nephritis (LN). METHODS: Serum LPS and CD14 levels were determined in LN patients and healthy subjects using commercially available assays. CD14 expression in LN kidney biopsies was examined with cytochemical staining. CD14-overexpressing HK-2 cells were generated and the role of CD14 in inflammatory and fibrotic processes investigated. RESULTS: Serum LPS and CD14 levels were significantly higher in LN patients compared to healthy subjects (P<0.05, for both). Kidney biopsies from active LN patients showed increased CD14 expression, predominantly in proximal tubular epithelial cells, compared with normal kidney tissue. CD14 overexpression did not affect cell proliferation in HK-2 cells, but was associated with increased IL-6 secretion and fibronectin expression, by 26.73±4.63 fold and 3.19±2.28 fold respectively. Upon stimulation with either LPS or endotoxin-free TGF-β1, CD14-overexpressing HK-2 cells showed further augmentation of IL-6 secretion and fibronectin expression (P<0.05, for all). In contrast, HK-2 cells deficient in CD14 showed attenuated fibronectin expression upon LPS or TGF-β1 stimulation. CONCLUSION: Our data show that active LN is accompanied by increased serum and renal tubular epithelial CD14 expression, and CD14 may contribute to LPS- or cytokine-dependent inflammatory and fibrotic processes in the setting of LN.