Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition.
Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition.
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DOI：
10.1126/scisignal.aal1601
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发表时间：
2018-03-06
影响因子：
7.3
通讯作者：
Lauffenburger DA
中科院分区：
文献类型：
--
作者：
Jones DS;Jenney AP;Joughin BA;Sorger PK;Lauffenburger DA
类风湿关节炎(RA)是一种慢性炎症性疾病，会导致关节疼痛、肿胀和功能丧失。事实证明，开发有效的新药具有挑战性，部分原因是细胞内信号网络的复杂性和互连性质，这使药物干预的效果复杂化。在这里，我们描述了在RA中被激活的信号通路，并评估了靶向抑制剂的多变量效应。RA患者的滑液激活了滑膜成纤维细胞(SFS)中的激酶信号通路JAK、JNK、p38和MEK，SFS是一种促进RA进展的基质细胞类型。激酶抑制剂以一种依赖于刺激环境的方式增强了“非靶标”通路的信号。例如，p38抑制剂在RA的临床试验中被广泛探索，在炎症性而不是有丝分裂的情况下，导致核因子κB(NFκB)、JNK和MEK信号在SFs中异常增加。CREB是一种转录因子，在MAPK信号的负反馈环路中发挥部分作用，成为这种上下文依赖性的关键调节因子。在炎症刺激下，CREB的激活主要由p38诱导，而在有丝分裂刺激下，则主要由MEK诱导；因此，针对p38或MEK的药物在有丝分裂和炎症条件下培养的SFs中的作用明显不同。综上所述，这些发现说明了刺激环境如何改变路径串扰，即使对于固定的网络拓扑，提示炎症环境中p38的串扰限制了p38抑制剂在RA中的益处，并进一步证明了在炎症相关疾病中仔细考虑p38靶向药物的必要性。
Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging, in part because of the complexities and interconnected nature of intracellular signaling networks, which complicate the effects of pharmacological interventions. Here, we characterized the signaling pathways that are activated in RA and evaluated the multivariate effects of targeted inhibitors. Synovial fluids from RA patients activated the kinase signaling pathways JAK, JNK, p38, and MEK in synovial fibroblasts (SFs), a stromal cell type that promotes RA progression. Kinase inhibitors enhanced signaling of “off-target” pathways in a manner dependent on stimulatory context. For example, p38 inhibitors, which have been widely explored in clinical trials for RA, resulted in undesirable increases in nuclear factor κB (NFκB), JNK, and MEK signaling in SFs in inflammatory, but not mitogenic, contexts. CREB, a transcription factor that functions in part within a negative feedback loop in MAPK signaling, emerged as a key regulator of this context-dependence. CREB activation was induced predominately by p38 in response to inflammatory stimuli but by MEK in response to mitogenic stimuli; the effects of drugs targeting p38 or MEK were therefore markedly different in SFs cultured in mitogenic or inflammatory conditions. Together these findings illustrate how stimulatory context can alter pathway cross-talk even for a fixed network topology, suggest cross-talk by p38 in inflammatory contexts limited the benefit of p38 inhibitors in RA, and furthermore demonstrate the need for careful consideration of p38-targeted drugs in inflammation-related disorders.
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影响因子：
24.8
作者：
Carmona-Rivera, Carmelo;Carlucci, Philip M.;Kaplan, Mariana J.
通讯作者：
Kaplan, Mariana J.
影响因子：
5.4
作者：
Casals-Casas, Cristina;Alvarez, Eva;Celada, Antonio
通讯作者：
Celada, Antonio
影响因子：
3
作者：
Fisk, Marie;Gajendragadkar, Parag R.;Cheriyan, Joseph
通讯作者：
Cheriyan, Joseph
影响因子：
11.4
作者：
Cheung, PCF;Campbell, DG;Cohen, P
通讯作者：
Cohen, P
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y