E74-like factor (ELF3) and NFκB regulate lipocalin-2 expression in chondrocytes

Abstract

The E74-like factor 3 (ELF3) is a transcription factor induced by inflammatory cytokines in chondrocytes that increases gene expression of catabolic and inflammatory mediators. Lipocalin-2 (LCN2) is a novel adipokine that negatively impacts articular cartilage, triggering catabolic and inflammatory responses in chondrocytes. Here, we investigated the control of LCN2 gene expression by ELF3 in the context of IL-1-driven inflammatory responses in chondrocytes. The interaction of ELF3 and NFκB in modulating LCN2 levels was also explored. LCN2 mRNA and protein levels, as well those of several other ELF3 target genes, were determined by RT-qPCR and Western blotting. Human primary chondrocytes, primary chondrocytes from wild type and Elf3 knockout mice, and immortalized human T/C-28a2 and murine ATDC5 cell lines were used in in vitro assays. The activities of various gene reporter constructs were evaluated by luciferase assays. Gene overexpression or knockdown was performed using specific expression vectors or siRNA technology, respectively. ELF3 overexpression transactivated the LCN2 promoter and increased the IL-1-induced mRNA and protein levels of LCN2, as well as the mRNA expression of other pro-inflammatory mediators, in human and mouse chondrocytes. We also identified a collaborative loop between ELF3 and NFκB that amplifies the induction of LCN2. Our findings show a novel role for ELF3 and NFκB in the induction of the pro-inflammatory adipokine LCN2, providing additional evidence of the interaction between ELF3 and NFκB in modulating inflammatory responses, and a better understanding of the mechanisms of action of ELF3 in chondrocytes.

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