Involvement of TWEAK and the NF-κB signaling pathway in lupus nephritis

Sun,Fang; Teng,Jian; Yu,Pengfei; Li,Wenshuang; Chang,Jing; Xu,Honglei

doi:10.3892/etm.2018.5711

Involvement of TWEAK and the NF-κB signaling pathway in lupus nephritis

Authors:
- Fang Sun
- Jian Teng
- Pengfei Yu
- Wenshuang Li
- Jing Chang
- Honglei Xu
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Affiliations: Department of Nephrology, Yantaishan Hospital, Yantai, Shandong 264000, P.R. China, Department of Respiratory Medicine, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China, Department of Internal Medicine, Laiyang Tuberculosis Prevention Institution, Laiyang, Shandong 265299, P.R. China
Published online on: January 5, 2018 https://doi.org/10.3892/etm.2018.5711
Pages: 2611-2619

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Abstract

Previous findings have identified that tumor necrosis factor‑related weak inducer of apoptosis (TWEAK) is associated with lupus nephritis (LN) activity status; however, the mechanism involved remains unclear. The present study aimed to investigate the roles of TWEAK and the nuclear factor (NF)‑κB signaling pathway in LN. TWEAK levels in the blood and urine of patients with LN or non‑LN systemic lupus erythematosus were measured by ELISA and compared with those in healthy controls. TWEAK expression and NF‑κB transcriptional activity in the kidney were detected by western blotting, and Ki‑67 and cluster of differentiation (CD) 68 expression were assessed using immunofluorescence. Additionally, human mesangial cells (HMCs) were cultured in vitro and divided into five groups: Normal control, TWEAK stimulus group, TWEAK + TWEAK blocking antibody, TWEAK + NF‑κB inhibitor (BAY 11‑7082) and TWEAK + combined (blocking antibody + BAY 11‑7082). Cell cycle activity and Ki‑67 expression in the HMCs were evaluated using flow cytometry, and cell induction of macrophage chemotaxis was determined by a Transwell assay. Levels of the inflammation‑associated factors interleukin (IL)‑6, monocyte chemotactic protein 1 (MCP‑1), chemokine ligand 5 (CCL5), IL‑8 and IL‑10 were also detected by reverse transcription‑quantitative polymerase chain reaction. It was observed that the urine levels of TWEAK in patients with LN were significantly elevated compared with those in the other groups (P<0.05). LN kidneys exhibited markedly increased cell proliferative ability, macrophage infiltration, TWEAK expression and NF‑κB transcriptional activity compared with normal kidneys. Furthermore, the results indicated that treatment with recombinant TWEAK notably enhanced NF‑κB transcriptional activity and significantly promoted cell proliferation and cell cycle activity (P<0.05), induced macrophage chemotaxis (P<0.05), significantly increased the expression of the chemotactic factors IL‑6, IL‑8, MCP‑1 and CCL5 (P<0.05), and significantly reduced anti‑inflammatory cytokine IL‑10 mRNA expression in HMCs (P<0.05), relative to normal controls. Accordingly, blocking TWEAK function or inhibiting NF‑κB activity reversed these effects. Collectively these data indicate that urine TWEAK may be considered as a novel biomarker of LN activity, and that blocking TWEAK function or NF‑κB activity may effectively alleviate glomerular mesangial cell proliferation and macrophage chemotaxis.

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