Krüppel-Like Factor 4 Is a Regulator of Proinflammatory Signaling in Fibroblast-Like Synoviocytes through Increased IL-6 Expression.

Xinjing Luo,Jiangwen Xie,Jie Chen,Xuanrong Mo,Yongfeng Chen,Jianwei Ruan,Guoju Lv

doi:10.1155/2016/1062586

Abstract

Human fibroblast-like synoviocytes play a vital role in joint synovial inflammation in rheumatoid arthritis (RA). Proinflammatory cytokines induce fibroblast-like synoviocyte activation and dysfunction. The inflammatory mediator Krüppel-like factor 4 is upregulated during inflammation and plays an important role in endothelial and macrophage activation during inflammation. However, the role of Krüppel-like factor 4 in fibroblast-like synoviocyte activation and RA inflammation remains to be defined. In this study, we identify the notion that Krüppel-like factor 4 is higher expressed in synovial tissues and fibroblast-like synoviocytes from RA patients than those from osteoarthritis patients. In vitro, the expression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes is induced by proinflammatory cytokine tumor necrosis factor-α. Overexpression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes robustly induced interleukin-6 production in the presence or absence of tumor necrosis factor-α. Conversely, knockdown of Krüppel-like factor 4 markedly attenuated interleukin-6 production in the presence or absence of tumor necrosis factor-α. Krüppel-like factor 4 not only can bind to and activate the interleukin-6 promoter, but also may interact directly with nuclear factor-kappa B. These results suggest that Krüppel-like factor 4 may act as a transcription factor mediating the activation of fibroblast-like synoviocytes in RA by inducing interleukin-6 expression in response to tumor necrosis factor-α.

Highlights

The autoimmune disease rheumatoid arthritis (RA) is characterized by persistent synovial inflammation and progressive joint destruction
room temperature (RT)-PCR and western blotting verified that Kruppel-like factor 4 (KLF4) is expressed in cultured fibroblast-like synoviocytes (FLSs) from patients with both RA and OA, and KLF4 expression was higher in RA than in OA (Figures 1(d) and 1(e))
Because KLF4 is induced by TNF-α and TNF-αinduced KLF4 expression corresponded to TNF-α-induced IL-6 expression in RA FLSs, we considered the possibility that KLF4 may regulate IL-6 expression

Summary

Introduction

The autoimmune disease rheumatoid arthritis (RA) is characterized by persistent synovial inflammation and progressive joint destruction. FLSs, resident mesenchymal cells in the joint synovium, respond to proinflammatory stimuli including tumor necrosis factor-α (TNFα) and interleukin-1 (IL-1) and exhibit features of inflammatory cells contributing to the pathogenesis of RA [1, 4]. RA FLSs produce several types of cytokines and chemokines, including interleukin-6 (IL-6), interleukin (IL-8), and macrophage inflammatory protein-1 (MIP-1). [5,6,7] Of these proinflammatory mediators, IL-6 is an acutephase inflammatory cytokine that plays a crucial role in joint inflammation and augments bone erosion in RA [8]. The transcription factor nuclear factor-kappa B (NF-κB) is activated in response to proinflammatory stimuli in RA FLSs and induces IL-6 gene expression [12]

Methods

Results

Conclusion