Molecular network analysis of endometriosis reveals a role for c-Jun-regulated macrophage activation.
Molecular network analysis of endometriosis reveals a role for c-Jun-regulated macrophage activation.
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DOI：
10.1126/scitranslmed.3007988
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发表时间：
2014-02-05
影响因子：
17.1
通讯作者：
Griffith LG
中科院分区：
文献类型：
--
作者：
Beste MT;Pfäffle-Doyle N;Prentice EA;Morris SN;Lauffenburger DA;Isaacson KB;Griffith LG
子宫内膜异位症的临床治疗受到症状严重程度、不同的手术表现和临床结果的多样性之间的复杂关系的限制。作为目视分类方案的补充，疾病活动的分子图谱可能会改进风险分层，以便更好地为治疗决策提供信息，并确定靶向治疗的新方法。在这里，我们利用网络分析炎症细胞内部和之间的信息流，以辨别表征患者亚群的共识行为。通过多重免疫分析对细胞因子图谱进行的非监督多变量分析发现，有一组患者具有与常见临床特征相关的13种升高的细胞因子的共同“共识特征”，但在仅通过形态表现确定的患者亚群中没有观察到。共识标记的浓缩分析加强了腹膜巨噬细胞渗透和激活的首要地位，这在体外培养中明显升高。尽管熟悉的核因子κB家族的靶点出现在共识标记的过度表达的转录结合位点中，但我们的分析为c-jun、c-Fos和AP-1效应分子对丝裂原相关激酶信号的贡献提供了以前未知的证据。它们在巨噬细胞驱动的炎症网络的传播中的关键作用通过对上游激酶的靶向抑制得到证实。总的来说，这些分析提供了临床上相关的炎症网络的体内验证，该网络可以作为指导子宫内膜异位症治疗决策的客观措施，并在未来可能为评估旨在抑制推动疾病进展的炎症机制的新型药物的有效性提供一个机械终点。
Clinical management of endometriosis is limited by the complex relationship between symptom severity, heterogeneous surgical presentations, and variability in clinical outcomes. As a complement to visual classification schemes, molecular profiles of disease activity may improve risk stratification to better inform treatment decisions and identify novel approaches to targeted treatment. Here, we employ a network analysis of information flow within and between inflammatory cells to discern consensus behaviors characterizing patient sub-populations. Unsupervised multivariate analysis of cytokine profiles quantified by multiplex immunoassays identified a subset of patients with a shared “consensus signature” of thirteen elevated cytokines that was associated with common clinical features, but was not observed among patient subpopulations defined by morphologic presentation alone. Enrichment analysis of consensus markers reinforced the primacy of peritoneal macrophage infiltration and activation, which was demonstrably elevated in ex vivo cultures. Although familiar targets of the NFκB family emerged among over-represented transcriptional binding sites for consensus markers, our analysis provides evidence for a previously unrecognized contribution from c-Jun, c-Fos, and AP-1 effectors of mitogen associated kinase signaling. Their crucial involvement in propagation of macrophage-driven inflammatory networks was confirmed via targeted inhibition of upstream kinases. Collectively, these analyses provide in vivo validation of a clinically relevant inflammatory network that may serve as an objective measure for guiding treatment decisions for endometriosis management, and in the future may provide a mechanistic endpoint for assessing efficacy of novel agents aimed at curtailing inflammatory mechanisms that drive disease progression.
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DOI：
10.1111/j.1471-0528.1980.tb04514.x
发表时间：
1980-01-01
期刊：
BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY
影响因子：
--
作者：
KONINCKX, PR;RENAER, M;BROSENS, IA
通讯作者：
BROSENS, IA
影响因子：
6.1
作者：
Gazvani, MR;Christmas, S;Kingsland, CR
通讯作者：
Kingsland, CR
影响因子：
6.7
作者：
Lebovic, DI;Mueller, MD;Taylor, RN
通讯作者：
Taylor, RN
DOI：
10.1016/s0889-8545(05)70302-8
发表时间：
1997-06-01
影响因子：
3.2
作者：
Eskenazi, B;Warner, ML
通讯作者：
Warner, ML
影响因子：
6.7
作者：
Kabut, Jacek;Kondera-Anasz, Zdzislawa;Mielczarek-Palacz, Aleksandra
通讯作者：
Mielczarek-Palacz, Aleksandra