REGULATION OF SOCS EXPRESSION IN MACROPHAGES IN RESPONSE TO BORRELIA AND IL-10

巨噬细胞中 SOCS 表达对疏螺旋体和 IL-10 的调节

• 批准号: 7958643
• 负责人: VIDA A DENNIS
• 金额: $ 6.01万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958643
• 关键词: Borrelia; Borrelia burgdorferi; Cells; Computer Retrieval of Information on Scientific Projects Database; Cytokine Inducible SH2-Containing Protein; Cytokine Signaling; DNA Binding; Disease; Funding; Grant; Immune response; Inflammation; Inflammatory; Institution; Interferon Type II; Interleukin-10; Life; Lyme Disease; Macrophage Activation; Mediator of activation protein; Mus; Nitric Oxide; Nuclear Translocation; Order Spirochaetales; OspA protein; Phase; Phosphorylation; Play; Primates; Production; Proteins; Regulation; Research; Research Personnel; Resources; Role; STAT1 gene; STAT1 protein; Signal Transduction; Source; Testing; Time; United States National Institutes of Health; cytokine; macrophage; outer surface lipoprotein; overexpression; response

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 recently demonstrated that stimulation of mouse J774 macrophages with either live Borrelia burgdorferi spirochetes (Bb) or Bb purified outer surface lipoprotein (L-OspA) alone or combined with IL-10 augmented the expression of the suppressor of cytokine signaling (SOCS)1 and SOCS3 in these cells. We hypothesized that the expression of SOCS1/SOCS3 induced by B. burgdorferi alone or together with IL-10 in macrophages is functionally important in the control of inflammation during the course of Lyme disease; SOCS1/SOCS3 would act as direct modulators of inflammatory cytokine signaling in macrophages. To test this hypothesis, we examined the ability of SOCS to inhibit the activation and DNA binding activities of phosphorylated STAT (signal transducer and activator of transcription) 1 protein in response to IFN-gamma. We focused on IFN-gamma signaling because this cytokine plays a pivotal role in the activation of macrophages during the initial phase of the immune response. Live Bb and L-OspA alone or combined with IL-10 did not activate the phosphorylation of STAT1 in macrophages at all time points examined (0-60 mins). However, these stimulants inhibited pSTAT1 activation by 2- to 5-fold in response to IFN-g. This correlated with the enhanced expression of SOCS1/SOCS3 induced in these cells by live Bb and L-OspA. Live Bb combined with IL-10, L-OspA alone or combined with IL-10 significantly (P 0.002 to 0004) inhibited the nuclear translocation of pSTAT1 in macrophages in response to IFN-gamma. SOCS overexpression in macrophages had no effect on nitric oxide (NO) production by IFN-gamma, suggesting that SOCS is not a mediator of NO production by IFN-gamma in macrophages. This study demonstrates that SOCS1/SOCS3 induced by B. burgdorferi may functionally suppress macrophage activation and interfere with the host immune response during the early phase of disease.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们最近证实，用活伯氏疏螺旋体螺旋体（Bb）或Bb纯化的外表面脂蛋白（L-OspA）单独或与IL-10组合刺激小鼠J774巨噬细胞增强了这些细胞中细胞因子信号传导抑制因子（SOCS）1和SOCS 3的表达。我们推测B.在莱姆病过程中，巨噬细胞中单独或与IL-10一起的伯氏螺旋体在控制炎症方面具有重要的功能; SOCS 1/SOCS 3将作为巨噬细胞中炎性细胞因子信号传导的直接调节剂。为了验证这一假设，我们研究了SOCS抑制磷酸化STAT（信号转导和转录激活因子）1蛋白响应IFN-γ的激活和DNA结合活性的能力。我们专注于IFN-γ信号传导，因为这种细胞因子在免疫应答的初始阶段在巨噬细胞的活化中起着关键作用。单独或与IL-10组合的活Bb和L-OspA在所有检查的时间点（0-60分钟）都没有激活巨噬细胞中STAT 1的磷酸化。然而，这些刺激物抑制pSTAT 1激活2- 5倍，响应于IFN-γ。这与在这些细胞中由活Bb和L-OspA诱导的SOCS 1/SOCS 3的表达增强相关。Live Bb联合IL-10、L-OspA单独或联合IL-10显著抑制巨噬细胞中pSTAT 1响应IFN-γ的核转位（P 0.002至0.004）。SOCS在巨噬细胞中的过表达对IFN-γ产生的一氧化氮（NO）没有影响，表明SOCS不是IFN-γ在巨噬细胞中产生NO的介质。本研究表明，B.在疾病的早期阶段，伯氏菌可在功能上抑制巨噬细胞活化并干扰宿主免疫应答。