SUPPRESSORS OF CYTOKINE SIGNALING AND IL-10 INHIBITORY EFFECT IN LYME DISEASE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。我们已经表明，白细胞介素-10（IL-10）抑制巨噬细胞响应伯氏疏螺旋体或其脂蛋白产生的炎性细胞因子。IL-10发挥这种抗炎作用的机制仍然未知。最近的研究表明，细胞因子信号转导抑制因子（SOCS）蛋白是由细胞因子和Toll样受体（TLR）介导的刺激诱导的，进而可以下调巨噬细胞中的细胞因子和TLR信号转导。因为已知SOCS是由IL-10和B诱导的。由于Burgdorferi/脂蛋白最可能通过TLR 2或异二聚体TLR 2/1和/或TLR 2/6相互作用，我们假设SOCS由IL-10和B诱导。在巨噬细胞中，IL-10可抑制伯氏菌/脂蛋白，并可介导IL-10对伴随引起的细胞因子的抑制。我们在这里报告，小鼠J774巨噬细胞与IL-10和添加B孵育。在伯氏螺旋体（冻融的、活的或超声处理的）中，脂化的外表面蛋白A（L-OspA）而非去脂化的OspA增强了它们的SOCS 1/SOCS 3 mRNA表达，其中SOCS 3更丰富。合成脂肽Pam 3Cys也在这些条件下诱导SOCS 1/SOCS 3。内源性IL-10和翻译抑制剂放线菌酮都不能阻断B诱导的SOCS 1/SOCS 3。burgdorferi/脂蛋白，表明不需要其他基因的表达。用IL-10和B共刺激巨噬细胞。Burgdorferi/脂蛋白也增加了SOCS 1/SOCS 3蛋白的表达。这与IL-10介导的炎症细胞因子IL-1？的抑制相关，IL-6、IL-12 p40、IL-18和TNF-？。我们的数据表明IL-10抑制由B引起的炎性细胞因子的能力。SOCS可能是IL-10在巨噬细胞中发挥抗炎作用的机制之一。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have shown that interleukin-10 (IL-10) inhibits inflammatory cytokines produced by macrophages in response to Borrelia burgdorferi or its lipoproteins. The mechanism by which IL-10 exerts this anti-inflammatory effect is still unknown. Recent findings indicate that suppressors of cytokine signaling (SOCS) proteins are induced by cytokines and Toll-like receptor (TLR)-mediated stimuli, and in turn can down-regulate cytokine and TLR signaling in macrophages. Because it is known that SOCS are induced by IL-10, and B. burgdorferi/lipoproteins most likely interact via TLR2 or the heterodimers TLR2/1 and/or TLR2/6, we hypothesize that SOCS are induced by IL-10 and B. burgdorferi/lipoproteins in macrophages, and may mediate the inhibition by IL-10 of concomitantly elicited cytokines. We report here that mouse J774 macrophages incubated with IL-10 and added B. burgdorferi spirochetes (freeze-thawed, live or sonicated), lipidated outer surface protein A (L-OspA) but not unlipidated OspA augmented their SOCS1/SOCS3 mRNA expression, with SOCS3 being the more abundant. Pam3Cys, a synthetic lipopeptide, also induced SOCS1/SOCS3 under these conditions. Neither endogenous IL-10 nor the translation inhibitor cycloheximide blocked SOCS1/SOCS3 induction by B. burgdorferi/lipoproteins, indicating the expression of other genes is not required. Co-stimulation of macrophages with IL-10 and B. burgdorferi/lipoproteins also augmented the expression of SOCS1/SOCS3 proteins. This correlated with the IL-10-mediated inhibition of the inflammatory cytokines IL-1?, IL-6, IL-12p40, IL-18 and TNF-?. Our data are evidence to suggest that the capacity of IL-10 to inhibit inflammatory cytokines elicited by B. burgdorferi/lipoproteins in macrophages depends on SOCS, and may provide a possible mechanism for the anti-inflammatory effects of IL-10 in this cont