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Compensation of Adiponectin-Induced Adenosine Monophosphate-Activated Protein Kinase and p38 Mitogen-Activated Protein Kinase Signaling in Rheumatoid Arthritis Synovial Fibroblasts
Journal of Interferon & Cytokine Research ( IF 2.3 ) Pub Date : 2021-05-17 , DOI: 10.1089/jir.2019.0204
Kiran Khawaja 1 , Klaus W Frommer 1 , Mona Bausch 1 , Stefan Rehart 2 , Ulf Müller-Ladner 1 , Elena Neumann 1
Affiliation  

Rheumatoid arthritis (RA) is a chronic inflammatory disorder marked by synovitis, ultimately leading to cartilage and bone destruction. In RA, adiponectin levels are increased in serum and synovial fluid. Adiponectin belongs to the adipokines, a group of highly bioactive substances secreted by adipocytes and other cell types. It has been shown to induce the production of proinflammatory and prodestructive factors by human RA synovial fibroblasts (RASF), suggesting a role in the pathophysiology of the disease. Although adenosine monophosphate-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK) are known to be involved in adiponectin signaling in RASF, no literature is available about whether the different adiponectin isoforms affect AMPK and p38 MAPK signaling in the same manner. In this study, we elucidated the signaling mechanisms in RASF, activated in response to selective stimulation with the 2 biologically most potent adiponectin isoforms, and possible approaches to inhibit adiponectin-mediated effects in RASF. All adiponectin isoforms induced p38 MAPK and AMPK phosphorylation to various degrees. Blocking AMPK activation increased p38 MAPK phosphorylation, while blocking p38 MAPK activation increased AMPK phosphorylation, both independent of the effect of adiponectin. Neither AMPKα1 nor AMPKα2 knockdown reduced interleukin (IL)-6/IL-8 release. Targeting transforming growth factor-activated kinase 1 (TAK1), a signaling molecule upstream of p38 MAPK, reduced the IL-6/IL-8 release. Taken together, our study showed that, in the case of adiponectin isoforms, inhibiting the p38 MAPK or the AMPK signaling pathway individually is not sufficient, probably due to compensatory interactions between these pathways. TAK1 might provide an alternative approach by ameliorating the proinflammatory effects of adiponectin in RA. Our results do not suggest that targeting individual adiponectin isoforms specifically in RA would provide a benefit over targeting adiponectin as a whole. However, whether targeting individual adiponectin isoforms would allow minimizing the loss of the beneficial effects of adiponectin within the metabolic and cardiovascular system still needs further investigation.

中文翻译:

脂联素诱导的一磷酸腺苷活化蛋白激酶和 p38 丝裂原活化蛋白激酶信号在类风湿性关节炎滑膜成纤维细胞中的补偿

类风湿性关节炎 (RA) 是一种以滑膜炎为特征的慢性炎症性疾病,最终导致软骨和骨骼破坏。在 RA 中,血清和滑液中的脂联素水平升高。脂联素属于脂肪因子,一组由脂肪细胞和其他细胞类型分泌的高生物活性物质。它已被证明可诱导人类 RA 滑膜成纤维细胞 (RASF) 产生促炎和促破坏因子,这表明它在该疾病的病理生理学中起作用。虽然已知一磷酸腺苷活化蛋白激酶 (AMPK) 和 p38 丝裂原活化蛋白激酶 (MAPK) 参与 RASF 中的脂联素信号传导,但没有关于不同脂联素同种型是否影响 AMPK 和 p38 MAPK 信号传导的文献方式。在这项研究中,我们阐明了 RASF 中的信号传导机制,响应于 2 种生物学上最有效的脂联素同种型的选择性刺激而激活,以及抑制 RASF 中脂联素介导的作用的可能方法。所有脂联素亚型均不同程度地诱导 p38 MAPK 和 AMPK 磷酸化。阻断 AMPK 活化增加 p38 MAPK 磷酸化,而阻断 p38 MAPK 活化增加 AMPK 磷酸化,两者均独立于脂联素的作用。AMPKα1 和 AMPKα2 敲低都不会降低白细胞介素 (IL)-6/IL-8 的释放。靶向 p38 MAPK 上游的信号分子转化生长因子激活激酶 1 (TAK1) 可减少 IL-6/IL-8 的释放。总之,我们的研究表明,对于脂联素异构体,单独抑制 p38 MAPK 或 AMPK 信号通路是不够的,可能是由于这些通路之间的补偿性相互作用。TAK1 可能通过改善脂联素在 RA 中的促炎作用提供一种替代方法。我们的结果并不表明专门针对 RA 中的单个脂联素同种型会比针对整个脂联素提供益处。然而,靶向单个脂联素异构体是否可以最大限度地减少脂联素在代谢和心血管系统中的有益作用的损失仍需要进一步研究。我们的结果并不表明专门针对 RA 中的单个脂联素同种型会比针对整个脂联素提供益处。然而,靶向单个脂联素异构体是否可以最大限度地减少脂联素在代谢和心血管系统中的有益作用的损失仍需要进一步研究。我们的结果并不表明专门针对 RA 中的单个脂联素同种型会比针对整个脂联素提供益处。然而,靶向单个脂联素异构体是否可以最大限度地减少脂联素在代谢和心血管系统中的有益作用的损失仍需要进一步研究。
更新日期:2021-05-19
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