Proinflammatory receptor switch from Gαs to Gαi signaling by β-arrestin-mediated PDE4 recruitment in mixed RA synovial cells
Proinflammatory receptor switch from Gαs to Gαi signaling by β-arrestin-mediated PDE4 recruitment in mixed RA synovial cells
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DOI：
10.1016/j.bbi.2015.07.020
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发表时间：
2015-11-01
影响因子：
15.1
通讯作者：
Straub, Rainer H.
中科院分区：
文献类型：
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作者：
Jenei-Lanzl, Zsuzsa;Zwingenberg, Janika;Straub, Rainer H.
目的：在慢性炎症中，通过抑制磷酸二酯酶-4 （PDE4）来预防cAMP的降解可作为抗炎治疗。然而，PDE4抑制对类风湿关节炎（RA）无效。最近的研究表明，PDE4/ β -抑制素在β -肾上腺素受体上的相互作用导致从G α s信号转换到G α i信号和ERK1/2激活。这样的信号转换可能会引起促炎作用。我们的目的是研究在RA和骨关节炎（OA）混合滑膜细胞中这种可能的G α s到G α i信号转换。方法：滑膜细胞单独或联合肾上腺素能、多巴胺能和腺苷能药物、罗利普朗（PDE4抑制剂）、G α i信号抑制剂（百日破毒素）和蛋白激酶A阻滞剂（PI(A)）。在常氧或缺氧条件下，促炎TNF是读数参数。我们通过成像技术研究了PDE4和β -阻滞蛋白的共表达和相互作用。western blotting分析pERK1/2的表达。结果：RA和OA混合滑膜细胞具有所有主要的G α - s偶联神经递质受体。在缺氧情况下，特别是在RA细胞中，G α - s偶联受体激动剂意外地增加TNF，而各自的拮抗剂则降低TNF。在缺氧条件下，罗利普兰单用或罗利普兰联合G α - s激动剂可使TNF升高，而百日咳毒素或PKA抑制可逆转这一作用。PDE4和β -抑制素在滑膜组织和细胞中的共定位和相互作用被证实。G α s激动剂或罗利普兰加G α s激动剂增加了pERK1/2的表达。结论：这项研究在人类关节炎滑膜组织中发现了一个意想不到的促炎转换，从G α s信号到G α i信号，这取决于PDE4/ β -抑制素的相互作用。这种现象很可能是导致PDE4抑制剂和G α 5激动剂在RA中的疗效降低的原因。(C) 2015爱思唯尔公司版权所有。
Objective: In chronic inflammation, prevention of cAMP degradation by phosphodiesterase-4 (PDE4) inhibition can be anti-inflammatory therapy. However, PDE4 inhibition was uneffective in rheumatoid arthritis (RA). Recent studies demonstrated that PDE4/beta-arrestin interaction at beta-adrenoceptors resulted in switching from G alpha s to G alpha i signaling and ERK1/2 activation. Such a switch in signaling might elicit proinflammatory effects. We aimed to investigate this possible G alpha s to G alpha i signaling switch in RA and osteoarthritis (OA) mixed synoviocytes.Methods: Synoviocytes were treated alone or with combinations of adrenergic, dopaminergic, and adenosinergic drugs, rolipram (PDE4 inhibitor), inhibitors of G alpha i signaling (pertussis toxin), and blockers of protein kinase A (PI(A). Under normoxic or hypoxic conditions, proinflammatory TNF was the readout-parameter. We investigated co-expression and interaction of PDE4 and beta-arrestin by imaging techniques. Expression of pERK1/2 was analyzed by western blotting.Results: Mixed synoviocytes in RA and OA possessed all major G alpha s-coupled neurotransmitter receptors. Under hypoxia, particularly in RA cells, G alpha s-coupled receptor agonists unexpectedly increased TNF and respective antagonists decreased TNF. Under hypoxia, rolipram alone or rolipram plus G alpha s agonists increased TNF, which was reversed by pertussis toxin or PKA inhibition. Co-localization and interaction of PDE4 and beta-arrestin in synovial tissue and cells was demonstrated. G alpha s agonists or rolipram plus G alpha s agonists increased pERK1/2 expression.Conclusions: This study in human arthritic synovial tissue presents an unexpected proinflammatory switch from G alpha s to G alpha i signaling, which depends on PDE4/beta-arrestin interaction. This phenomenon is most probably responsible for reduced efficacy of PDE4 inhibitors and G alpha s agonists in RA. (C) 2015 Elsevier Inc. All rights reserved.