Pim-2/mTORC1 Pathway Shapes Inflammatory Capacity in Rheumatoid Arthritis Synovial Cells Exposed to Lipid Peroxidations.

Geng Yin,Yan Li,Qi-Bing Xie,Xiao-Min Cen,Min Yang

doi:10.1155/2015/240210

Abstract

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of multiple joints, with disruption of joint cartilage. The proliferation of synovial fibroblasts in response to multiple inflammation factors is central to the pathogenesis of rheumatoid arthritis. Our previous studies showed that 4-HNE may induce synovial intrinsic inflammations by activating NF-κB pathways and lead to cell apoptosis. However, the molecular mechanisms of how synovial NF-κB activation is modulated are not fully understood. Here, the present findings demonstrated that 4-HNE may induce synovial intrinsic inflammations by mTORC1 inactivation. While ectopic activation of mTORC1 pathway by the overexpression of Pim-2 may disrupt the initiation of inflammatory reactions and maintain synovial homeostasis, our findings will help to uncover novel signaling pathways between inflammations and oxidative stress in rheumatoid arthritis development and imply that Pim-2/mTORC1 pathway may be critical for the initiation of inflammatory reactions in human rheumatoid arthritis synovial cells.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovium that can lead to severe joint damage [1]
Considering that mammalian target of rapamycin complex 1 (mTORC1) pathway is a key regulator of innate inflammatory homeostasis in several types of cells [16], we investigated mTORC1 activities by 4-HNE treatment in MH7A rheumatoid arthritis synovial cells
Our results revealed that lipid peroxidation may inhibit mTORC1 pathway in synoviocytes, which may confer to the development of inflammations

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovium that can lead to severe joint damage [1]. The central pathogenesis of rheumatoid arthritis is the proliferation of fibroblast-like synoviocytes (FLSs) in response to stimulators [2, 3]. During the process of FLSs proliferation, inflammatory responses are critical for rheumatoid arthritis development [4, 5]. Synovial inflammatory responses are mainly induced by products of autocrine, and paracrine molecules produced by infiltrating mononuclear cells, such as tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β, IL-6, and IL-17 [5]. The initiation and proceeding of inflammatory reactions might be critical for rheumatoid arthritis development. Since inflammatory reactions are important for synovial homeostasis, the precise regulation of inflammation must be well achieved. It has been long appreciated that NF-κB is a significant transcription factor that functions in immune and inflammatory responses, stress responses, apoptosis, and differentiation.

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Results

Conclusion