KLF4 downregulates FGF21 to activate inflammatory injury and oxidative stress of LPS‑induced ATDC5 cells via SIRT1/NF‑κB/p53 signaling

Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory disease. Transcriptional regulation of fibroblast growth factor 21 (FGF21) by the transcription factor Krüppel-like factor 4 (KLF4) serves an important role in chronic inflammatory disease. However, to the best of our knowledge, the role of both these factors in AS has not been previously reported. In the present study, ATDC5 cells were induced by lipopolysaccharide (LPS) to establish an AS inflammatory injury model. The expression levels of FGF21 and KLF4 were detected using reverse transcription-quantitative PCR and western blotting. Cell transfection was performed to alter the expression levels of KLF4 and FGF21. Subsequently, the regulatory effects and mechanisms underlying KLF4 and FGF21 on oxidative stress and inflammation in AS were investigated by performing Cell Counting Kit-8 assays, ELISAs, TUNEL staining and western blotting. Moreover, the expression levels of sirtuin 1 (SirT1)/nF-κB/p53 pathway-related proteins were detected via western blotting. FGF21 overexpression promoted LPS-induced viability on ATDC5 cells, inhibited lPS-induced apoptosis, and decreased the lPS-induced inflammatory response and oxidative stress levels of ATDC5 cells. Overexpression of the transcription factor KLF4 reversed the protective effect of FGF21 overexpression on LPS-induced inflammatory injury in ATDC5 cells. The results suggested that this process may be achieved via regulating the SirT1/nF-κB/p53 signaling pathway. Overall, the present study demonstrated that KLF4 downregulates FGF21 to activate inflammatory injury and oxidative stress of LPS-induced ATDC5 cells via SIRT1/NF-κB/p53 signaling.

Usp25 Upregulation Boosts GSDMD-Mediated Pyroptosis of Acinar Cells in Acute Pancreatitis

“…The subsequent rescue experiment revealed that KLF4 overexpression facilitated inflammation and pyroptosis of AP acinar cells. In line with our data, KLF4 upregulation increased the levels of oxidative stress markers and proinflammatory cytokines in LPS-treated ATDC5 cells in ankylosing spondylitis (52), and KLF4 deficiency imparts an anti-inflammation role in dextran sodium sulfate–triggered colitis (53). Moreover, decreased KLF4 expression diminishes pyroptosis of Ang-II–treated vascular smooth muscle cells by blocking the PI3K/AKT signaling pathway (54).…”

The Mechanism of “Treating Different Diseases with the Same Treatment” by Qiangji Jianpi Decoction in Ankylosing Spondylitis Combined with Inflammatory Bowel Disease: A Comprehensive Analysis of Multiple Methods

“…The results of the GO enrichment analysis showed that biological processes were mainly related to the relevance of organismal responses, such as the response to oxidative stress, lipopolysaccharides, and reactive oxygen species. A recent in vitro study on ankylosing spondylitis found that KLF4 downregulates FGF21 via the SIRT1/NF- κ B/p53 signaling pathway to activate LPS-induced inflammatory damage and oxidative stress in ATDC5 cells [ 50 ]. There was also evidence that excessive inflammatory responses and oxidative stress are thought to be the main features of inflammatory bowel disease [ 51 ].…”

MAPK Is a Mutual Pathway Targeted by Anxiety-Related miRNAs, and E2F5 Is a Putative Target for Anxiolytic miRNAs

“…KLF4 transactivated the cyclin-dependent kinase inhibitor 1A (CDKN1A) promoter, where CDKN1A is involved in cell apoptosis and upregulated in the hippocampus of anxious mice [ 48 , 49 ]. Through SIRT1/NF-κB/p53 signaling, KLF4 activates inflammatory injury and oxidative stress in LPS-induced ATDC5 (chondrogenic cell line) cells [ 50 ]. Studies on inflammation and oxidative stress have shown that KLF4 may cause anxiety through changes in the physiology of the brain [ 51 , 52 ].…”