Oleksy Aneta, Banbula Agnieszka, Bugno Marcin, Travis James, Potempa Jan
Institute of Molecular Biology, Jagellonian University, Krakow, Poland
Microb Pathog. 2002 Apr;32(4):173-81. doi: 10.1006/mpat.2002.0491.
Current consensus is that periodontitis is an infectious disease in which a deregulated chronic inflammatory reaction not only may lead to periodontal tissue damage but also eventually may cause tooth loss. In controlling the inflammatory state the interplay between a network of cytokines and their receptors plays an important role. Here we show that the interleukin-6 receptor (IL-6R) is rapidly and efficiently inactivated by gingipains, the arginine- (HRgpA and RgpB) and lysine- (Kgp) specific cysteine proteinases from Porphyromonas gingivalis. Preincubation of HepG2 cells with active gingipains results in the loss of gp80 (CD126) from the cell surface. This also correlates with a decreased responsiveness to stimulation by interleukin-6 (IL-6), as determined by measurement of the status of IL-6R-mediated STAT 3 (Signal Transducer and Activator of Transcription 3) activation by this cytokine. Significantly, incubation of cells with gingipains was not accompanied by release of the soluble receptor, indicating its degradation, and this was confirmed by susceptibility of the recombinant, soluble receptor to proteolytic digestion by these enzymes. With the exception of the degradation of soluble IL-6R (sIL-6R) by Kgp, all of these reactions were also observed in the presence of serum suggesting that receptor inactivation may occur in vivo. Interestingly, Kgp, although less effective in cleaving sIL-6R, was able to decrease cell responsiveness to IL-6, possibly through degradation/inactivation of the signal transducing component (gp130) associated with IL-6R. These data, together with previous observation that IL-6 itself is inactivated by gingipains, suggest that at periodontitis sites infected by P. gingivalis the inflammatory reactions dependent on IL-6 could be severely hindered contributing to both tissue damage and periodontopathogen survival.
目前的共识是，牙周炎是一种感染性疾病，其中失调的慢性炎症反应不仅可能导致牙周组织损伤，最终还可能导致牙齿脱落。在控制炎症状态方面，细胞因子及其受体网络之间的相互作用起着重要作用。在这里，我们表明白细胞介素-6受体（IL-6R）被牙龈蛋白酶迅速而有效地失活，牙龈蛋白酶是牙龈卟啉单胞菌产生的精氨酸特异性（HRgpA和RgpB）和赖氨酸特异性（Kgp）半胱氨酸蛋白酶。用活性牙龈蛋白酶预孵育HepG2细胞会导致细胞表面gp80（CD126）丢失。这也与白细胞介素-6（IL-6）刺激的反应性降低相关，这是通过测量该细胞因子介导的IL-6R介导的STAT 3（信号转导和转录激活因子3）激活状态来确定的。值得注意的是，用牙龈蛋白酶孵育细胞并未伴随可溶性受体的释放，表明其降解，重组可溶性受体对这些酶的蛋白水解消化的敏感性证实了这一点。除了Kgp对可溶性IL-6R（sIL-6R）的降解外，在有血清存在的情况下也观察到了所有这些反应，这表明受体失活可能在体内发生。有趣的是，Kgp虽然在切割sIL-6R方面效果较差，但能够降低细胞对IL-6的反应性，可能是通过降解/失活与IL-6R相关的信号转导成分（gp130）。这些数据，连同先前观察到的IL-6本身被牙龈蛋白酶失活的结果，表明在被牙龈卟啉单胞菌感染的牙周炎部位，依赖IL-6的炎症反应可能会受到严重阻碍，从而导致组织损伤和牙周病原体存活。
