CP-25 combined with MTX/ LEF ameliorates the progression of adjuvant-induced arthritis by the inhibition on GRK2 translocation

Yang, Xiaofang; Zhao, Yingjie; Jia, Xiaoyi; Wang, Chun; Wu, Yujing; Zhang, Lingling; Cao, Yan; Wei, Wei

doi:10.1016/j.biopha.2018.12.040

Cited by 46 publications

(47 citation statements)

References 42 publications

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“…Excessive desensitization of β-adrenergic receptors mediated by GRK2 resulted in a loss of cardiomyocyte contractile reserve. In RA, our previous study confirmed that in the FLS of adjuvant induced arthritis (AA) rats, continuous stimulation of PGE2 promoted GRK2 transferring to membrane [13,15,16], which induced the over-desensitization of EP4 and downregulated the level of cAMP [15]. Based on these above studies, we speculated that in the macrophages of RA, continuous stimulation of PGE2 on EP4 may result in the translocation of GRK2 to membrane, leading to the over-desensitization of EP4, reduction of cAMP.…”

Section: Introductionmentioning

confidence: 62%

“…PMs were plated into sterile Petri dishes and incubated in DMEM supplemented with 10% FBS. PMs were incubated at 37 • C with 5% CO 2 and harvested after 2 h [16]. BMMs were isolated from the femurs of mice.…”

Section: Cells Isolation and Cell Culturementioning

confidence: 99%

“…The total protein preparation: PMs, BMMs and RAW were lysed and centrifuged at 14,000× g for 15 min at 4 • C. Collecting the supernatant and added the protein loading buffer (5×), then the sample was boiled for 8 min. These samples were used to detect the expression of EP1-EP4, iNOS, Arg1, p-CREB, CREB and β-actin [16].…”

Section: Protein Sample Preparationmentioning

confidence: 99%

“…Membrane protein expression: PMs, BMMs and RAW were lysed and centrifuged at 14,000× g for 15 min at 4 • C. Collecting the supernatant and centrifuged at 100,000× g for 1 h at 4 • C. Removing the supernatant, the precipitated membrane protein was resuspended by 50 µL cell lysis buffer and 10 µL protein loading buffer (5×), then the sample was boiled for 5 min. These samples were used to detect the membrane expression of EP4, GRK2 and ATPA1 [15,16].…”

Section: Protein Sample Preparationmentioning

confidence: 99%

“…The membranes were scanned with an ImageQuant LAS 4000 (GE Healthcare (Little Chalfont, Buckinghamshire, UK).) and analysed used ImageJ software (NIH) [16].…”

Section: Western Blot Analysesmentioning

confidence: 99%

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GRK2 Mediated Abnormal Transduction of PGE2-EP4-cAMP-CREB Signaling Induces the Imbalance of Macrophages Polarization in Collagen-Induced Arthritis Mice

Yang

Zhao

et al. 2019

Cells

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Rheumatoid arthritis (RA) is characterized by the massive infiltration of various chronic inflammatory cells in synovia. In synovial fluid of patients with RA, M1 macrophages are dominant among all subtypes of macrophages, the mechanisms of macrophages polarization imbalance in RA has not been fully illuminated. The prostaglandin E2 (PGE2) augments M2 polarization in part via the cyclic adenosine monophosphate (cAMP)-cyclic AMP responsive element binding (CREB) signaling. However, previous study found constant stimulus of PGE2 on fibroblast-like synovial cells of adjuvant arthritis rats induced the decrease of cAMP, which is primarily caused by G protein-coupled receptor kinase 2 (GRK2)-induced EP4 over- desensitization. Whether GRK2 mediated-EP4 over-desensitization reduces the level of cAMP and inhibits M2 polarization in RA is unclear. Here we observed M1 macrophages were dominant in peritoneal macrophages (PMs), bone-marrow-derived macrophages (BMMs) and synovial macrophages of collagen-induced arthritis (CIA) mice. PGE2 stimulated M2 polarization via the EP4-cAMP-CREB in normal mice, while failed to promote M2 polarization in the PMs of CIA mice. Further, we found the EP4 over-desensitization stimulated by PGE2 induced abnormal PGE2-cAMP-CREB signaling as well as the imbalance of macrophage polarization. Targeted disruption of GRK2 in Raw264.7 (RAW) through GRK2 siRNA or CRISPR/Cas9 downregulated the M1 macrophage markers, upregulated the M2 macrophage markers and the EP4 membrane localization. The reduced M1/M2 ratio and increased p-CREB expression were observed in BMMs and PMs of GRK2+/− mice. This study highlighted a novel role of GRK2 in regulating macrophages function in RA and provided new idea for precision treatment of RA.

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Section: Introductionmentioning

confidence: 62%

Section: Cells Isolation and Cell Culturementioning

confidence: 99%

Section: Protein Sample Preparationmentioning

confidence: 99%

Section: Protein Sample Preparationmentioning

confidence: 99%

“…The membranes were scanned with an ImageQuant LAS 4000 (GE Healthcare (Little Chalfont, Buckinghamshire, UK).) and analysed used ImageJ software (NIH) [16].…”

Section: Western Blot Analysesmentioning

confidence: 99%

See 3 more Smart Citations

GRK2 Mediated Abnormal Transduction of PGE2-EP4-cAMP-CREB Signaling Induces the Imbalance of Macrophages Polarization in Collagen-Induced Arthritis Mice

Yang

Zhao

et al. 2019

Cells

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CP‐25 exerts therapeutic effects in mice with dextran sodium sulfate‐induced colitis by inhibiting GRK2 translocation to downregulate the TLR4‐NF‐κB‐NLRP3 inflammasome signaling pathway in macrophages

et al. 2021

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Deficiency of G protein‐coupled receptor kinase 2 (GRK2) was found to protect mice from dextran sulfate sodium (DSS)‐induced colitis. Paeoniflorin‐6′‐O‐benzene sulfonate (CP‐25) has been shown to exert anti‐inflammatory immune regulatory effects in animal models of inflammatory autoimmune disease. This study aimed to investigate the of GRK2 in the pathogenesis of ulcerative colitis (UC) and its effects on macrophage polarization, macrophage subtype regulation of intestinal barrier function, and therapeutic effects of CP‐25 in mice with DSS‐induced colitis. We found imbalanced macrophage polarization, intestinal barrier dysfunction, and abnormal activation of GRK2 and TLR4‐NF‐κB‐NLRP3 inflammasome signaling pathway in the colonic mucosa of patients with UC. CP‐25, restored the damaged intestinal barrier function by inhibiting the transmembrane region of GRK2 in macrophages stimulated by lipopolysaccharides. CP‐25 exerted therapeutic effects by ameliorating clinical manifestation, regulating macrophage polarization, and restoring abnormally activated TLR4‐NF‐κB‐NLRP3 inflammasome signaling pathway by inhibiting GRK2. These data suggest the pathogenesis of UC may be related to the imbalance of macrophage polarization, which leads to abnormal activation of TLR4‐NF‐κB‐NLRP3 inflammasome signaling pathway mediated by GRK2 and destruction of the intestinal mucosal barrier. CP‐25 confers therapeutic effects on colitis by inhibiting GRK2 translocation to induce the downregulation of TLR4‐NF‐κB‐NLRP3 inflammasome signaling in macrophages.

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Paeoniflorin‐6′‐o‐benzene sulfonate (CP‐25) improves vasculitis through inhibiting IL‐17A/JAK/STAT3 signaling pathway in endothelial cells of HFD CIA rats

Cai

et al. 2020

Phytotherapy Research

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Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects not only joints but also multiple organ systems including cardiovascular system. Endothelial dysfunction plays an important role in cardiovascular diseases (CVD). In RA, endothelial dysfunction exists at both the macrovascular and the microvascular levels, which is a precursor to vasculitis. This study aimed to investigate the pathogenesis of vasculitis and the therapeutic effect of CP‐25 on vasculitis in high‐fat diet (HFD) collagen‐induced arthritis (CIA) rats. Experimental groups were divided into normal group, HFD group, CIA group, HFD CIA group, CP‐25 group and MTX group. In vitro, IL‐17A was used to stimulate human umbilical vein endothelial cells (HUVECs), and then CP‐25 was used to intervene. Results showed that CP‐25 reduced global scoring (GS), arthritis index (AI), and swollen joint count (SJC) scores, improved histopathological score, reduced T cells percentage, and decreased IL‐17A and ICAM‐1 levels. Besides, CP‐25 reduced the expression of p‐STAT3 to normal levels in vascular of HFD CIA rats. In vitro, IL‐17A promoted the expression of p‐JAK1, p‐JAK2, p‐JAK3, pSTAT3, and ICAM‐1, and CP‐25 inhibited the expression of p‐JAK1, p‐JAK2, p‐JAK3, p‐STAT3, and ICAM‐1. In conclusion, CP‐25 might inhibit endothelial cell activation through inhibiting IL‐17A/JAK/STAT3 signaling pathway, which improves vasculitis in HFD CIA rats.

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CP-25 combined with MTX/ LEF ameliorates the progression of adjuvant-induced arthritis by the inhibition on GRK2 translocation

Cited by 46 publications

References 42 publications

GRK2 Mediated Abnormal Transduction of PGE2-EP4-cAMP-CREB Signaling Induces the Imbalance of Macrophages Polarization in Collagen-Induced Arthritis Mice

GRK2 Mediated Abnormal Transduction of PGE2-EP4-cAMP-CREB Signaling Induces the Imbalance of Macrophages Polarization in Collagen-Induced Arthritis Mice

CP‐25 exerts therapeutic effects in mice with dextran sodium sulfate‐induced colitis by inhibiting GRK2 translocation to downregulate the TLR4‐NF‐κB‐NLRP3 inflammasome signaling pathway in macrophages

Paeoniflorin‐6′‐o‐benzene sulfonate (CP‐25) improves vasculitis through inhibiting IL‐17A/JAK/STAT3 signaling pathway in endothelial cells of HFD CIA rats

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