The roles of MKP-1 in Gram-negative bacterial sepsis and colitis

MKP-1 在革兰氏阴性细菌败血症和结肠炎中的作用

• 批准号: 7736051
• 负责人: Yusen Liu
• 金额: $ 32.4万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736051
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Applications Grants; Attention; Award; Bacteria; Bacterial Infections; Businesses; Calendar; Characteristics; Chronic; Code; Colitis; Communication; Confidentiality; Containment; Crohn' s disease; Data; Defect; Development; Devices; Disclosure; Documentation; Education; Electronic Mail; Enterobacteriaceae; Enterocolitis; Escherichia coli; Exhibits; Feedback; Foundations; Funding; Genes; Gram-Negative Bacterial Infections; Grant; Grant Review; House mice; Human; Human Resources; Human Subject Research; IACUC; Immune; Immune response; Immune system; Infection; Infection prevention; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Institution; Interleukin-10; Interleukin-6; Intestines; Invaded; Knock-out; Knockout Mice; Lead; Letters; Life; Ligands; MAPK14 gene; MAPK8 gene; Mails; Mesentery; Mitogen-Activated Protein Kinases; Molecular; Mus; National Institute of Allergy and Infectious Disease; Organ failure; Organism; Participant; Pathogenesis; Peptidoglycan; Phagocytes; Phagocytosis; Phenotype; Phosphoric Monoester Hydrolases; Play; Policies; Printing; Process; Production; Protein phosphatase; Published Comment; Rectal Prolapse; Reliance; Research Ethics Committees; Role; Sampling; Scanning; Sepsis; Septic Shock; Serum; Services; Severities; Shock; Specialist; System; Telefacsimile; Telephone; Testing; Text; Toll-like receptors; Ulcerative Colitis; United States National Institutes of Health; Wild Type Mouse; antimicrobial; bactericide; base; cytokine; human disease; interleukin-23; killings; lipoteichoic acid; microbial; mortality; mouse model; neutralizing antibody; novel; novel strategies; pathogen; public health relevance; response; treatment strategy; web site

DESCRIPTION (provided by applicant): Dysregulation of the inflammatory response plays an important role in the pathogenesis of a plethora of human diseases, including septic shock and inflammatory bowel disease (IBD). Mitogen-activated protein kinase phosphatase (MKP)-1 is crucial for restraining the inflammatory response during bacterial infection. MKP-1 acts as an inducible negative regulator of p38 and JNK, and serves to restrict the production of pro-inflammatory cytokines. MKP-1-deficient (MKP-1-/-) mice exhibit a more robust inflammatory response than do wild-type mice when challenged with both toll-like receptor ligands and bacteria. Since inflammation facilitates the containment and clearance of microbial pathogens, we reasoned that MKP-1-/- mice should exhibit more efficient killing of invading pathogens. Surprisingly, when infected with Escherichia coli, MKP-1-/- mice exhibited substantially greater bacterial burdens than do wild-type mice in spite of a more robust inflammatory response. These data suggest that MKP-1 not only functions as a crucial anti-inflammatory regulator but also plays an important role in orchestrating the bactericidal activity of the innate immune mechanism. In addition to inflammatory cytokines, MKP-1-/- mice also produce substantially higher levels of the anti-inflammatory cytokine IL-10. This led us to hypothesize that excessive IL-10 production impairs the antimicrobial defense in MKP-1-/- mice. To understand the role of IL-10 in MKP-1-/- mice, we generated mice that lack both the IL-10 and MKP-1 genes. IL-10-/- mice housed in conventional but not pathogen-free conditions are known to develop colitis associated with rectal prolapse. Conversely, deletion of both MKP-1 and IL-10 caused severe rectal prolapse even in pathogen-free conditions. The MKP-1/IL-10 double knockout mice also developed ocular abnormalities, a novel phenotype resembling the ocular manifestation of IBD. Taken together, these data suggest that MKP-1 deficiency exacerbates the colitis phenotype of IL-10-/- mice. We propose to define the molecular mechanisms underlying the bactericidal defects of MKP-1-/- mice and to define the role of MKP-1 in the pathogenesis of colitis using the IL-10-/- mouse model of IBD. Our specific aims are to determine: 1). The defects in the innate immune system underlying the faulty bactericidal activity of MKP-1-/- mice; 2) Whether excessive IL-10 production contributes to the defects in the bactericidal activity of MKP-1-/- mice; and 3) Whether MKP-1 deficiency exacerbates the severity of colitis in IL-10-/- mice. The proposed studies will unravel critical regulatory mechanisms that govern the immune response to infection and prevent chronic enterocolitis and may lead to novel strategies for the treatment of sepsis and IBD. PUBLIC HEALTH RELEVANCE: Abnormal immune responses are a major cause of human illnesses, including septic shock and inflammatory bowel disease. In this grant application we propose to study the roles of MKP-1 in Gram-negative bacterial sepsis and colitis. These studies will uncover critical immune regulatory mechanisms, and may lead to novel strategies for the treatment of sepsis and inflammatory bowel disease.

描述（由申请人提供）：炎症反应的失调在多种人类疾病的发病机制中发挥着重要作用，包括脓毒性休克和炎症性肠病（IBD）。丝裂原激活蛋白激酶磷酸酶 (MKP)-1 对于抑制细菌感染期间的炎症反应至关重要。 MKP-1 充当 p38 和 JNK 的诱导型负调节因子，并用于限制促炎细胞因子的产生。当受到 Toll 样受体配体和细菌的攻击时，MKP-1 缺陷型 (MKP-1-/-) 小鼠表现出比野生型小鼠更强烈的炎症反应。由于炎症促进微生物病原体的遏制和清除，我们推断 MKP-1-/- 小鼠应该表现出更有效地杀死入侵病原体。令人惊讶的是，当感染大肠杆菌时，尽管炎症反应更强烈，但 MKP-1-/- 小鼠的细菌负荷比野生型小鼠要大得多。这些数据表明 MKP-1 不仅充当重要的抗炎调节剂，而且在协调先天免疫机制的杀菌活性中发挥着重要作用。除了炎症细胞因子外，MKP-1-/- 小鼠还产生显着更高水平的抗炎细胞因子 IL-10。这使我们推测过量的 IL-10 产生会损害 MKP-1-/- 小鼠的抗菌防御能力。为了了解 IL-10 在 MKP-1-/- 小鼠中的作用，我们培育了同时缺乏 IL-10 和 MKP-1 基因的小鼠。已知饲养在常规条件但非无病原体条件下的 IL-10-/- 小鼠会患上与直肠脱垂相关的结肠炎。相反，即使在无病原体的条件下，MKP-1和IL-10的缺失也会导致严重的直肠脱垂。 MKP-1/IL-10 双基因敲除小鼠还出现眼部异常，这是一种类似于 IBD 眼部表现的新表型。综上所述，这些数据表明 MKP-1 缺乏会加剧 IL-10-/- 小鼠的结肠炎表型。我们建议定义 MKP-1-/- 小鼠杀菌缺陷的分子机制，并使用 IBD IL-10-/- 小鼠模型来定义 MKP-1 在结肠炎发病机制中的作用。我们的具体目标是确定：1​​）。先天免疫系统的缺陷导致 MKP-1-/- 小鼠的杀菌活性错误； 2) IL-10产生过多是否导致MKP-1-/-小鼠杀菌活性缺陷； 3) MKP-1 缺乏是否会加剧 IL-10-/- 小鼠结肠炎的严重程度。拟议的研究将揭示控制感染免疫反应和预防慢性小肠结肠炎的关键调节机制，并可能带来治疗脓毒症和炎症性肠病的新策略。 公共卫生相关性：异常的免疫反应是人类疾病的主要原因，包括败血性休克和炎症性肠病。在这项拨款申请中，我们建议研究 MKP-1 在革兰氏阴性细菌败血症和结肠炎中的作用。这些研究将揭示关键的免疫调节机制，并可能带来治疗脓毒症和炎症性肠病的新策略。