Lipid Peroxidation‐Mediated Inflammation Promotes Cell Apoptosis through Activation of NF‐κB Pathway in Rheumatoid Arthritis Synovial Cells

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of multiple joints. The central pathogenesis of RA is the proliferation of synovial fibroblasts in response to inflammatory cytokines. However, some of the targeted therapies for inflammation reactions do not display significant clinical improvement after initiation of therapy. Thus, the relationship between inflammatory responses and RA therapy is still incompletely understood. In the present study, we proposed to determine whether enhanced inflammations may lead to cell apoptosis in rheumatoid arthritis synoviocytes. Our results indicated that products of lipid peroxidations, 4-HNE, may induce synovial intrinsic inflammations by activating NF-κB pathways and it may lead to cell apoptosis. Pharmacological inhibition of NF-κB activation may reduce the 4-HNE mediated inflammation responses and subsequent cell apoptosis. Our results may help to clarify the role of inflammations on RA development and imply that blocking NF-κB activation may be partly beneficial for human RA therapy. These findings might provide a mechanism-based rationale for developing new strategy to RA clinical therapy.

The role of heme oxygenase-1 (HO-1) in the regulation of inflammatory reaction, neuronal cell proliferation and apoptosis in rats after intracerebral hemorrhage (ICH)

“…Among these, NF-κB signaling pathway is the most frequently studied 29,30. NF-κB belongs to the family of Rel protein, which comprises of two subunits, p50 and p65.…”

“…Under stimulation of the apoptotic signal or inflammatory factors, IκB degrades after phosphorylation and separates with NF-κB p65. NF-κB p65 enters into nucleus, phosphorylates at serine 536 site, further regulates the expression of its target proteins such as Bax, Bcl-2, Caspase 3, TNF-α, IL-1β and IL-6, and mediates the apoptosis and inflammatory reaction 29,30…”

Age-associated up-regulation of EGR1 promotes granulosa cell apoptosis during follicle atresia in mice through the NF-κB pathway

“…39 For example, a recent study indicated that 4-HNE may induce synovial intrinsic inflammations and apoptosis by activating NF-kB signaling. 40 In addition, EGR1 has been shown to activate a range of pro-inflammatory cytokines, including TNFa, IL-1, IL-2 and IL-6, through the NF-kB pathway upon LPS exposure. 41 In the present study, an increase in NF-kB phosphorylation (p-NFkB) was identified in GCs with EGR1 up-regulation in vitro.…”

Anti-Inflammatory Effects of TRAF-Interacting Protein in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

“…In addition, FLS can promote various processes in RA by secreting different types of inflammatory cytokines, such as IL-6, IL-8, IL-1 β , TNF α , and MCP-1, and matrix metalloproteinases (MMPs), such as MMP-1 and MMP-13, which has been shown to be closely related to the activation of cellular mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF- κ B) signaling pathways [6–9]. Because of the pivotal roles of FLS in the pathogenesis of RA, recent studies have reported that it could be potential approaches for the treatment of RA, mainly through the modulation of activities of various essential adaptors and nuclear transcriptional factors in the inflammation relevant signaling pathways in FLS [10–14]. …”