Berberine Modulates LPA Function to Inhibit the Proliferation and Inflammation of FLS-RA via p38/ERK MAPK Pathway Mediated by LPA₁

Abstract

Objective This study aimed to investigate whether berberine exerted anti-inflammatory and antiproliferative effects on the fibroblast-like synoviocytes of rheumatoid arthritis (FLS-RA) through regulating the lysophosphatidic acid (LPA) function. Methods Firstly, the expression levels of LPA and lysophosphatidic acid receptor 1 (LPA1) in RA patients, osteoarthritis (OA) patients, and healthy controls were detected. Moreover, molecular docking was employed to characterize the binding sites of berberine in the predicted protein targets. Later, FLS-RA were stimulated using berberine, LPA, and the specific inhibitor (Ki16425) of LPA1, thereafter, the effects on the proliferation, apoptosis, the release of inflammatory mediators of FLS-RA, and the MAPK pathway were observed. Results Compared with healthy controls (n = 25), the plasma LPA level (n = 28) and synovial fluid (n = 10) were markedly higher in RA patients. LPA1 was highly expressed in RA patients (n = 4) relative to that in OA patients (n = 4). Berberine remarkably inhibited the proliferation and the excessive production of IL-6 and TNF-α in FLS-RA, whereas suppressing the expression of K-ras, c-Raf, and p-38/ERK-phosphorylation. In addition, berberine inhibited the LPA-induced p-38/ERK-phosphorylation through binding to LPA1. Conclusions LPA plays a certain role in promoting the proliferation and inflammation of FLS-RA. Berberine potentially modulates LPA function to suppress the proliferation and inflammation of FLS-RA through blocking the p38/ERK MAPK pathway mediated by LPA1. These findings suggest that, berberine possesses potential lipid-regulating, antiarthritis, and synovial hyperplasia inhibition activities against RA, which may provide a promising therapeutic target for the clinical drug development for RA patients with dyslipidemia and high CVD risk.

Involvement of p38 MAPK in Synaptic Function and Dysfunction

“…Moreover, the identification of roles independent of infections led to the extension of what has been called "sterile inflammation" (e.g., injury, illness, or aging). In particular, the activity of p38α has been associated with (a) the progression of the expression of protein markers of the aging phenotype [20][21][22]; (b) the development of inflammation and oxidative stress [10,23] associated with neurodegeneration, including Alzheimer's [24][25][26], lipopolysaccharide (LPS) [27,28], and Parkinson's [29,30] diseases; cardiovascular [31] and musculoskeletal diseases; diabetes [32]; rheumatoid arthritis [33]; and toxin-induced preterm birth [34]. Importantly, small molecule inhibitors of the p38 MAPK family have been developed, and show efficacy in blocking the production of proinflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor alpha (TNF-α) [35].…”

Immunomodulatory effects of berberine on the inflamed joint reveal new therapeutic targets for rheumatoid arthritis management

“…71 The levels of plasma and synovial LPA in RA patients are found to be significantly higher than those in healthy subjects. 77 LPA is suggested to be an independent risk factor of synovial hyperplasia in RA in addition to the high burden of inflammation. 77 During inflammation, LPA is majorly generated in activated platelets through the degradation of lysophosphatidylcholine by secretory lysophospholipase D termed as autotaxin (ATX) that is detected to be highly elevated in the activated arthritic synovial fluid from RA patients and AIA rats, 77,78 and berberine has been indicated to decrease the expression of ATX in RAFLS cells and thus decrease LPA levels in RA condition.…”

A Novel Therapeutic Reagent, KA-1002 for Alleviating Lysophosphatidic Acid-Mediated Inflammation Related Gene Expression in Swine Macrophages

“…In the previous report [27,28], downstream of LPA receptor activation, MAPK/ERK signaling pathway can be activated by LPA. In our study, we found that LPA treatment on swine macrophages strongly induced biological pathway for "role of MAPK signaling in the pathogenesis of influenza" and its related genes to be differentially regulated (Figure 3).…”

“…We also identified KA-1002 treatment downregulated LPA-induced gene enrichment set of "role of MAPK signaling in the pathogenesis of influenza" (Figure 3). MAPK signaling is well-known for its role in inflammation [28]. However, the gene enrichment set of "IL-10 signaling" was increased by KA-1002 treatment compared to LPA mediated inflamed swine macrophages (Figure 3).…”