PDF(Pubmed)
Abstract：
Tumor progression locus 2 (Tpl2) is a serine-threonine kinase known to promote inflammation in response to various pathogen-associated molecular patterns (PAMPs), inflammatory cytokines and G-protein-coupled receptors and consequently aids in host resistance to pathogens. We have recently shown that Tpl2-/- mice succumb to infection with a low-pathogenicity strain of influenza (x31, H3N2) by an unknown mechanism. In this study, we sought to characterize the cytokine and immune cell profile of influenza-infected Tpl2-/- mice to gain insight into its host protective effects. Although Tpl2-/- mice display modestly impaired viral control, no virus was observed in the lungs of Tpl2-/- mice on the day of peak morbidity and mortality suggesting that morbidity is not due to virus cytopathic effects but rather to an overactive antiviral immune response. Indeed, increased levels of interferon-β (IFN-β), the IFN-inducible monocyte chemoattractant protein-1 (MCP-1, CCL2), Macrophage inflammatory protein 1 alpha (MIP-1α; CCL3), MIP-1β (CCL4), RANTES (CCL5), IP-10 (CXCL10) and Interferon-γ (IFN-γ) was observed in the lungs of influenza-infected Tpl2-/- mice at 7 days post infection (dpi). Elevated cytokine and chemokines were accompanied by increased infiltration of the lungs with inflammatory monocytes and neutrophils. Additionally, we noted that increased IFN-β correlated with increased CCL2, CXCL1 and nitric oxide synthase (NOS2) expression in the lungs, which has been associated with severe influenza infections. Bone marrow chimeras with Tpl2 ablation localized to radioresistant cells confirmed that Tpl2 functions, at least in part, within radioresistant cells to limit pro-inflammatory response to viral infection. Collectively, this study suggests that Tpl2 tempers inflammation during influenza infection by constraining the production of interferons and chemokines which are known to promote the recruitment of detrimental inflammatory monocytes and neutrophils.
摘要：
肿瘤进展基因座2（Tpl2）是一种丝氨酸-苏氨酸激酶，已知可促进各种病原体相关分子模式（PAMPs）的炎症反应。炎性细胞因子和G蛋白偶联受体，因此有助于宿主对病原体的抗性。我们最近表明，Tpl2-/-小鼠以未知的机制死于低致病性流感株（x31，H3N2）的感染。在这项研究中,我们试图表征流感感染的Tpl2-/-小鼠的细胞因子和免疫细胞谱,以深入了解其宿主保护作用.虽然Tpl2-/-小鼠表现出适度受损的病毒控制，在Tpl2-/-小鼠的肺中,在发病和死亡高峰当天未观察到病毒,提示发病不是由于病毒致细胞病变作用,而是由于过度活跃的抗病毒免疫应答.的确,干扰素-β（IFN-β）水平升高，IFN诱导的单核细胞趋化蛋白-1（MCP-1，CCL2），巨噬细胞炎性蛋白1α(MIP-1α;CCL3),MIP-1β(CCL4),RANTES(CCL5),在感染后7天(dpi),在流感感染的Tpl2-/-小鼠的肺中观察到IP-10(CXCL10)和干扰素-γ(IFN-γ)。升高的细胞因子和趋化因子伴随着炎性单核细胞和嗜中性粒细胞对肺的浸润增加。此外,我们注意到IFN-β的增加与肺中CCL2，CXCL1和一氧化氮合酶（NOS2）表达的增加相关，这与严重的流感感染有关。骨髓嵌合体与Tpl2消融定位于放射抗性细胞证实Tpl2功能，至少在某种程度上,在放射抗性细胞内限制对病毒感染的促炎反应。总的来说，这项研究表明,Tpl2通过限制干扰素和趋化因子的产生来缓和流感感染期间的炎症,已知干扰素和趋化因子可促进有害的炎性单核细胞和中性粒细胞的募集.
