Stephanou A, Conroy S, Isenberg D A, Maione D, Poli V, Ciliberto G, Latchman D S
Department of Molecular Pathology, Windeyer Institute of Medical Sciences, University College London Medical School, London, UK.
J Autoimmun. 1998 Jun;11(3):249-53. doi: 10.1006/jaut.1998.0194.
Treatment of human peripheral blood lymphocytes (PBL) in vitro with the cytokine interleukin-6 (IL-6) induces increased levels of the 90 kDa heat shock protein (hsp90). Hsp90 levels are also elevated in PBLs of human patients with systemic lupus erythematosus (SLE) and in MRL/lpr mice with autoimmune disease. Although IL-6 is elevated in both these situations it has not been shown that it is involved in stimulating elevation of hsp90 levels in vivo. Here we show directly that the elevation of IL-6 in vivo either in mice transgenic for the IL-6 gene or in knock-out mice lacking a functional gene for the transcription factor C/EBP beta (NF-IL-6) does indeed result in elevated hsp90 levels. This overexpression is associated with the specific production of autoantibodies to hsp90 in these mice which is also observed in SLE patients and MRL/1pr mice. Hence IL-6 is likely to play a critical role in the regulation of hsp90 levels both in autoimmune disease states and potentially in normal cells in vivo. In turn the elevated levels of hsp90 produced in autoimmune diseases are likely to be responsible for the observed production of anti-hsp90 autoantibodies.
在体外用人细胞因子白细胞介素-6（IL-6）处理人外周血淋巴细胞（PBL），可使90kDa热休克蛋白（hsp90）水平升高。系统性红斑狼疮（SLE）患者的PBL以及患有自身免疫性疾病的MRL/lpr小鼠的PBL中，hsp90水平也会升高。尽管在这两种情况下IL-6水平均升高，但尚未证实其在体内刺激hsp90水平升高过程中发挥作用。在此我们直接表明，在IL-6基因转基因小鼠或缺乏转录因子C/EBPβ（NF-IL-6）功能基因的敲除小鼠体内，IL-6升高确实会导致hsp90水平升高。这种过表达与这些小鼠体内针对hsp90的自身抗体的特异性产生相关，这在SLE患者和MRL/1pr小鼠中也有观察到。因此，IL-6可能在自身免疫性疾病状态以及体内正常细胞中hsp90水平的调节中发挥关键作用。反过来，自身免疫性疾病中产生的hsp90水平升高可能是观察到的抗hsp90自身抗体产生的原因。
