Beneficial Effects of Chemokines in Liver

趋化因子是一类具有广泛生物活性的低分子量细胞因子。虽然最初 作为白细胞化学引诱物，趋化因子现在被认为影响许多生理学特性。 包括器官发生、肿瘤生长和转移、淋巴细胞运输和创伤的过程 治愈由趋化因子控制的两个主要过程是细胞迁移和细胞增殖;最近， 然而，肝脏中的数据表明趋化因子保护免受急性形式的毒性损伤。的 趋化因子的细胞保护作用被公认为是一个肽亚家族， CXC。CXC趋化因子的有益特性尚未完全表征。记录了 CXC趋化因子对肝细胞的有益作用和阐明其作用机制是 本提案的主要目标。我们的基本假设是CXC趋化因子抑制肝细胞 凋亡设计实验来表征体内和细胞培养中的这种抗凋亡作用， 使用半乳糖胺和内毒素作为模型肝毒素。特别重要的是， CXCR 2 +/+和CXCR 2-/-小鼠之间的骨髓嵌合体，这是区分 趋化因子对肝细胞的保护作用 化学引诱物分离肝细胞研究旨在记录CXC趋化因子受体 在肝细胞中的表达，使用实时PCR、FACS和监测趋化因子诱导的信号传导。 进一步的研究将集中在趋化因子阻止细胞凋亡的机制上。迄今为止的调查结果 指出PI-3激酶的活化是该过程中的关键步骤。实验将检查相关的抗- PI-3激酶活化，特别是Akt的磷酸化，NF-κ B的活化， 和Bcl-xL的上调。总而言之，拟议的研究将提供有关活动的全面看法 肝脏中CXC趋化因子的水平。发现CXC趋化因子的潜在益处至关重要， 因为这些化合物的中和被认为是治疗炎症的临床方法， 疾病如果趋化因子具有显著的细胞保护作用，那么抗趋化因子治疗可能是有效的。 还有不必要的副作用

Chemokines are low molecular-weight cytokines with a wide range of biological activities. Although initially characterized as leukocyte chemoattractants, chemokines are now recognized to influence many physiologic processes including organogenesis, tumor growth and metastasis, lymphocyte trafficking and wound healing. The two major processes governed by chemokines are cell migration and cell proliferation; recent data in liver, however, suggest that chemokines protect against acute forms of toxic injury. The cytoprotective role of chemokines has been putatively assigned to one subfamily of peptides designated CXC. The beneficial properties of CXC chemokines have not been fully characterized. Documenting the salutary effects of CXC chemokines toward liver cells and elucidating their mechanism of action are the primary objectives of this proposal. Our fundamental hypothesis is that CXC chemokines inhibit hepatocyte apoptosis. Experiments are designed to characterize this anti-apoptotic effect in vivo and in cell culture, using galactosamine and endotoxin as a model hepatotoxin. Particularly important are studies involving bone marrow chimeras between CXCR2 +/+ and CXCR2 -/- mice, which are necessary to distinguish the cytoprotective effects of chemokines toward hepatocytes in vivo from their activity as leukocyte chemoattractants. Studies in isolated hepatocytes are intended to document CXC chemokine receptor expression in hepatocytes, using real-time PCR, FACS, and monitoring of chemokine-induced signaling. Additional studies will focus on the mechanism by which chemokines prevent apoptosis. Findings to date point to activation of PI-3 kinase as a critical step in this process. Experiments will examine relevant anti- apoptotic consequences of PI-3 kinase activation, specifically phosphorylation of Akt, activation of NF-kB, and up-regulation of Bcl-xL. In sum, the proposed studies will provide a comprehensive view of the activity of CXC chemokines in liver. Uncovering a potential benefit of CXC chemokines is of critical importance, because neutralization of these compounds is being considered as a clinical approach to inflammatory diseases. If chemokines have significant cytoprotective effects, then anti-chemokine therapy may be complicated by unwanted side effects.