Negative Regulation of Innate Immune Responses through MAPK Phosphatases

MAPK 磷酸酶对先天免疫反应的负调控

基本信息

批准号：
7575125
负责人：
Keith L Kirkwood
金额：
$ 33.55万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-07 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7575125
关键词：
3&apos Untranslated Regions Abbreviations Acid Phosphatase Actinobacillus actinomycetemcomitans Acute Address Adenosine Adult Alveolar Bone Loss Attenuated BRF1 gene Binding Proteins Biological Assay Bone Marrow Cells Chronic Classification Data Development Dinoprostone Disease Disease Progression Elements Experimental Models Extracellular Signal Regulated Kinases Family Gene Targeting Goals Granulocyte-Macrophage Colony-Stimulating Factor Green Fluorescent Proteins Growth Immune Immune response Immunohistochemistry In Vitro Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Interleukin-6 Interleukins Lipopolysaccharides MAP Kinase Gene MAPK phosphatase MAPK14 gene MAPK8 gene Matrix Metalloproteinases Mitogen-Activated Protein Kinases Modeling Molecular Mus NF-kappa B Nature Oral Organism Osteoclasts PTGS2 gene Pathway interactions Periodontal Diseases Periodontitis Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Process Production Protein Kinase Rattus Regulation Research Personnel Resistance Role Signal Pathway Signal Transduction Site Stress System TIS11 protein TNFSF11 gene Tissues Toll-like receptors Tumor Necrosis Factor-alpha Tumor Necrosis Factors Uridine Wild Type Mouse X-Ray Computed Tomography ZFP36L2 gene attenuation base bone bone loss butyrate response factor 1 collagenase 3 cyclooxygenase 2 cytokine fetal human ZFP36L2 protein in vivo mRNA Expression mRNA Stability macrophage mitogen-activated protein kinase p38 oral pathogen osteoclastogenesis pathogen programs prototype receptor response stress-activated protein kinase 1

项目摘要

DESCRIPTION (provided by applicant): Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. The production of inflammatory cytokines is a highly regulated process involving transcriptional and posttranscriptional mechanisms. One of the major signaling pathways activated by periopathogenic LPS in p38 MARK. Following p38 phosphorylation, inactivation of p38 MAP kinases is achieved mainly by a family of dual-specific MAP kinase phosphatases (MKP). MKP-1 is capable of negatively regulating both transcriptional and post transcriptional p38 MAP kinase activity. MKP-1 contributes towards LPS tolerance and over-expression of MKP-1 has shown to accelerate p38 inactivation resulting in diminished proinflammatory cytokine production. We have recently shown that LPS-induced IL-6 mRNA stability expression requires p38 signaling. Preliminary data for this proposal indicates that in MKP- 1 transfected cells, LPS-induced IL-6 expression is significantly attenuated. In addition, we have provided significant data showing the p38 is a major signaling pathway contributing to LPS-induced periodontal bone destruction. Based upon these data, we hypothesize that the endogenous negative regulator mechanism of p38 signaling, MKP-1, is a key component of responsible for attenuation of LPS-induced inflammatory cytokine expression in macrophages. In this proposal, the ability of TIP over-expression to decrease inflammation will be determined in vitro using gene targeted strategies in macrophages, and in vivo using experimental periodontitis models. The specific aims are 1) To determine the role of over-expressed MKP-1 on IL-6 and TNFa mRNA expression in vitro. 2) To determine the contribution of MKP-1 in ontogeny of inflammatory cytokine production and LPS-induced osteoclastogenesis in primary bone marrow macrophages and 3) To determine the impact of MKP-1 in inflammatory bone destruction in vivo using MKP mice. These studies will establish the role of LPS-induced cytokine expression and negative regulation in inflammatory bone loss through selective attenuation of p38 MAPK-induced signaling in periodontal bone destruction.

描述（由申请人提供）：牙周疾病的启动和进展是由于对口腔病原体的宿主免疫反应而发生的。炎症细胞因子的产生是一个高度调节的过程，涉及转录和转录后机制。由p38 mark中的围栏致病性LP激活的主要信号通路之一。 p38磷酸化后，p38 MAP激酶的灭活主要是通过双特异性MAP激酶磷酸酶（MKP）的家族来实现的。 MKP-1能够负调节转录和转录后P38 MAP激酶活性。 MKP-1有助于LPS耐受性和MKP-1的过表达，已表明会加速p38灭活，从而导致促炎细胞因子产生降低。我们最近表明，LPS诱导的IL-6 mRNA稳定性表达需要p38信号传导。该提案的初步数据表明，在MKP-1转染的细胞中，LPS诱导的IL-6表达显着减弱。此外，我们提供了重要的数据，显示p38是导致LPS诱导的牙周骨骼破坏的主要信号通路。基于这些数据，我们假设p38信号传导MKP-1的内源性负调节机制是负责衰减巨噬细胞中LPS诱导的炎性细胞因子表达的关键组成部分。在此提案中，使用巨噬细胞中的基因靶向策略在体外和使用实验性牙周炎模型的体内确定尖端过表达减少炎症的能力。具体目的是1）确定过表达MKP-1在体外IL-6和TNFA mRNA表达中的作用。 2）确定MKP-1在炎性细胞因子产生的个体发育中的贡献和LPS诱导的一骨骨髓巨噬细胞中的破骨细胞生成和3）确定MKP-1在使用MKP小鼠中MKP-1对体内炎症性骨破坏的影响。这些研究将通过选择性衰减p38 MAPK诱导的信号传导在牙周骨骼破坏中，确定LPS诱导的细胞因子表达和负调控在炎症性骨质流失中的作用。