Jog Neelakshi R, Caricchio Roberto
Rheumatology Section, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
Rheumatology Section, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
Clin Immunol. 2015 Jul;159(1):13-22. doi: 10.1016/j.clim.2015.04.009. Epub 2015 Apr 26.
We showed previously that 17β estradiol (E2) led to improved survival in nephrotoxic serum induced nephritis (NTN) in male mice. In this study we determined whether E2 regulates vascular cell adhesion molecule (VCAM)-1, an adhesion molecule that is upregulated in kidney during autoimmune nephritis, in mesangial cells (MC). We show that E2 inhibited VCAM-1 up-regulation in kidneys in vivo during NTN, and in MCs upon TNFα stimulation. VCAM-1 up-regulation in MCs was controlled by the transcription factor NFκB. E2 inhibited RNA polymerase II recruitment to the VCAM-1 promoter, but not p65 recruitment. Interestingly E2 inhibited TNFα stimulated interaction between poly (ADP-ribose) polymerase-1 (PARP-1) and p65. As PARP-1 is required for VCAM-1 upregulation in MCs, our data suggest that E2 may inhibit pre-initiation complex formation at VCAM-1 promoter by inhibiting PARP-1 recruitment to p65. We propose that E2 plays an important role in regulating renal inflammation locally.
我们之前表明，17β-雌二醇（E2）可提高雄性小鼠肾毒性血清诱导性肾炎（NTN）的存活率。在本研究中，我们确定E2是否调节系膜细胞（MC）中的血管细胞黏附分子（VCAM）-1，该黏附分子在自身免疫性肾炎期间在肾脏中上调。我们发现E2在NTN期间可抑制体内肾脏中VCAM-1的上调，以及在肿瘤坏死因子α（TNFα）刺激下MC中VCAM-1的上调。MC中VCAM-1的上调受转录因子核因子κB（NFκB）控制。E2抑制RNA聚合酶II募集至VCAM-1启动子，但不抑制p65的募集。有趣的是，E2抑制TNFα刺激的聚（ADP-核糖）聚合酶-1（PARP-1）与p65之间的相互作用。由于PARP-1是MC中VCAM-1上调所必需的，我们的数据表明E2可能通过抑制PARP-1募集至p65来抑制VCAM-1启动子处的起始前复合物形成。我们认为E2在局部调节肾脏炎症中起重要作用。
