Lindenkamp Christopher, Plümers Ricarda, Osterhage Michel R, Vanakker Olivier M, Van Wynsberghe Judith, Knabbe Cornelius, Hendig Doris
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, Germany.
Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
Biomedicines. 2023 Sep 29;11(10):2673. doi: 10.3390/biomedicines11102673.
Previous studies revealed a link between inflammation and overactivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling in syndromes associated with aging. Pseudoxanthoma elasticum (PXE), a rare autosomal-recessive disorder, arises from mutations in (). On a molecular level, PXE shares similarities with Hutchinson-Gilford progeria syndrome, such as increased activity of senescence-associated- beta-galactosidase or high expression of inflammatory factors. Thus, this study's aim was the evaluation of activated STAT3 and the influence of JAK1/2-inhibitor baricitinib (BA) on inflammatory processes such as the complement system in PXE. Analysis of activation of STAT3 was performed by immunofluorescence and Western blot, while inflammatory processes and complement system factors were determined based on mRNA expression and protein level. Our results assume overactivation of JAK/STAT3 signaling, increased expression levels of several complement factors and high C3 protein concentration in the sera of PXE patients. Supplementation with BA reduces JAK/STAT3 activation and partly reduces inflammation as well as the gene expression of complement factors belonging to the C1 complex and C3 convertase in PXE fibroblasts. Our results indicate a link between JAK/STAT3 signaling and complement activation contributing to the proinflammatory phenotype in PXE fibroblasts.
先前的研究揭示了炎症与衰老相关综合征中Janus激酶（JAK）/信号转导子和转录激活子（STAT）信号过度激活之间的联系。弹性假黄瘤（PXE）是一种罕见的常染色体隐性疾病，由（）中的突变引起。在分子水平上，PXE与哈钦森-吉尔福德早衰综合征有相似之处，比如衰老相关β-半乳糖苷酶活性增加或炎症因子高表达。因此，本研究的目的是评估STAT3的激活情况以及JAK1/2抑制剂巴瑞替尼（BA）对PXE中补体系统等炎症过程的影响。通过免疫荧光和蛋白质印迹法分析STAT3的激活情况，而炎症过程和补体系统因子则根据mRNA表达和蛋白质水平来确定。我们的结果表明PXE患者血清中JAK/STAT3信号过度激活、几种补体因子的表达水平增加以及C3蛋白浓度升高。补充BA可降低JAK/STAT3的激活，并部分减轻炎症以及PXE成纤维细胞中属于C1复合物和C3转化酶的补体因子的基因表达。我们的结果表明JAK/STAT3信号与补体激活之间存在联系，这导致了PXE成纤维细胞中的促炎表型。
