4‐Phenylbutyric acid, a potent endoplasmic reticulum stress inhibitor, attenuates the severity of collagen‐induced arthritis in mice via inhibition of proliferation and inflammatory responses of synovial fibroblasts

Abstract

4-Phenylbutyric acid (4-PBA) exerts potent pharmacological effects, including antiinflammatory properties, via inhibition of endoplasmic reticulum (ER) stress. However, it is not known whether 4-PBA attenuates the severity of rheumatoid arthritis. The present study aimed to determine whether the inhibition of ER stress by 4-PBA ameliorated experimentally induced arthritis. The proliferation of synovial fibroblasts (SFs) and expression of matrix metalloproteinases (MMPs) were evaluated in the presence of interleukin (IL)-1β with or without 4-PBA. The effect of 4-PBA on the phosphorylation of Mitogenactivated protein kinase (MAPK) and the activation of Nuclear factor-κB (NF-κB) in IL-1βstimulated SFs was assessed. In an in vivo study, the effects of 4-PBA were investigated using DBA/1 mice with collagen-induced arthritis (CIA). Clinical, histological, and serological assessments of CIA treated with 4-PBA were performed to determine the therapeutic effect of 4-PBA. In vitro, 4-PBA inhibited the proliferation and expression of IL-1βstimulated SFs and MMP-1 and MMP-3 through the suppression of both the phosphorylation of MAPKs and NF-κB in IL-1β-stimulated SFs. The 4-PBA treatment markedly attenuated the severity of arthritis in CIA mice. The 4-PBA treatment ameliorated joint swelling and the degree of bone erosion and destruction and decreased the level of inflammatory cytokines and MMP-3 and Cox-2. Furthermore, remarkable improvements in histopathological findings occurred in 4-PBA-treated mice. These findings suggested that 4-PBA could attenuate the severity of arthritis in CIA mice by partially blocking the phosphorylation of MAPKs and the activation of NF-κB in SFs. Thus, through the inhibition of ER stress, 4-PBA may be a potent agent for the treatment of RA.

MbovP0725, a secreted serine/threonine phosphatase, inhibits the host inflammatory response and affects metabolism in Mycoplasma bovis

“…A previous study demonstrated that 9-HODE is a pro-inflammatory mediator through the GPR132 receptor on monocytes and macrophages ( 46 ). In addition, 4-phenylbutyric acid is known to inhibit ER stress and reduce the levels of inflammatory mediators ( 47 ). Interestingly, some of the glycolytic enzymes have multiple functions in metabolism.…”

Quercetin alleviates cadmium-induced BRL-3A cell apoptosis by inhibiting oxidative stress and the PERK/IRE1α/ATF6 signaling pathway

“…1B), and 4-PBA (Figs. 1C and 1D) from previous studies and repeated experiments [21,23] . The signi cant reduction in cell viability in the Cd treated group demonstrates the important toxic effect of Cd on hepatocyte injury (Fig.…”

“…4-Phenylbutyrate (4-PBA) can promote protein folding; it is a chaperone protein and considered an ERS inhibitor because it can promote the folding of unfolded proteins [19,20] . Studies have shown that ERS is the pathogenesis of many diseases, and 4-PBA exhibits the ability to alleviate ERS [21] . Research has demonstrated that as a chaperone of unfolded proteins, 4-PBA can rescue cells from apoptosis by reducing ERS [22] .…”