Normal and UV-Induced cutaneous antigen presenting cells

正常和紫外线诱导的皮肤抗原呈递细胞

• 批准号: 7193429
• 负责人: Kevin D Cooper
• 金额: $ 25.39万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7193429
• 关键词: Acute; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Area; Behavior; Binding; Boxing; C3 Deficiency; C3bi; CD80 gene; Carcinogenesis Mechanism; Cell Differentiation process; Cell Lineage; Cell Maturation; Cells; Chemicals; Class; Clinical; Complement; Complement Degradation; Contact Sensitizing Agents; Cutaneous; Cytokine Inducible SH2-Containing Protein; DNA; Data; Dendritic Cells; Deposition; Development; Dinitrofluorobenzene; Dominant-Negative Mutation; Equilibrium; Exhibits; Exposure to; Extracellular Signal Regulated Kinases; Family; Generations; Genes; Home environment; Human; Immune; Immune response; Immunization; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; In Vitro; Infection; Infiltration; Injury; Interleukin 6 Receptor; Interleukin-10; Interleukin-12; Interleukin-6; Intervention; Knockout Mice; Light; Link; MAP Kinase Signaling Pathways; MAP2K6 gene; MAPK14 gene; MEKKs; MEKs; Maintenance; Marines; Mediating; Mitogen-Activated Protein Kinases; Modeling; Modification; Mus; Mutate; PD-98059; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Population; Predisposition; Principal Investigator; Production; Protein Overexpression; Proteins; Publications; Receptor Signaling; Recruitment Activity; Regulation; Research; Role; SB 203580; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Site; Skin; Solar Energy; Surface; System; T memory cell; T-Cell Activation; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic immunosuppression; Time; Translating; Tumor Antigens; UV Radiation Exposure; UV induced; antigen processing; crosslink; cytokine; human MAPK14 protein; immunogenic; in vivo; in vivo Model; interest; keratinocyte; kinase inhibitor; mRNA Expression; macrophage; member; microbial; mitogen-activated protein kinase p38; monocyte; mutant; novel; oncostatin M; prevent; programs; receptor; response; restoration; tumor; ultraviolet irradiation

UV injury dramatically changes the microenvironment of the skin causing distinct monocyte(Mo) behavior in normal and UV in vivo milieus. The post UV milieu promotes Mo-macrophages(Mph) and suppresses dendritic cell(DC) antigen presenting cells(APC's) maturation. UV-induced immunosuppression is associated with complement component iC3b deposition in the skin, and reversal of immunosuppression occurs in mice treated with antibodies to CD1 lb(an iC3b receptor on immunosuppressive Mo APC's), and in mice treated with sCRl(prevents iC3b formation). Mo exposed to iC3b model the in vivo situation; they are induced to express Mo/Mph features and are arrested in DC development, yet retain DC precursor potential. Recent data suggest that the p38 MAP kinase signaling pathway is involved in DC maturation, counterbalanced by ERK MAP kinase, and that CD1 lb engagement by antibodies activates ERK. Thus, it was interesting in our preliminary data that MAPK signaling pathway-induced transcipts were very prominently upregulated following iC3b engagement of monocyte CD1 lb. Also very prominently upregulated was the Oncostatin M/IL-6 family receptor/SOCS3 signaling pathway, which can preferentially promote Mph over DC, and which interacts with ERK. Thus, the hypothesis to be tested is whether these signaling pathways represent the critical mechanism by which iC3b mediates Mo differentiation and, ultimately, UV-induced immune suppression. Aim I examines MAPK activation and utilizes chemical and dominant negative MAPK inhibitors and MAPK overexpression strategies to determine if iC3b critically alters the balance of p38/ERK signaling during Mo differentiation. Aim II tests whether the SOCS3/IL6 receptor family signaling cascade is critically involved in the mechanism of iC3b modification of Mo precursors to DC and Mph's, and the linkage of MAPK's in the pathway. Aim III translates these findings in vivo to confirm their role in integrated immune response regulation, leading to novel immunotherapeutic strategies with clinical impact.

紫外线损伤极大地改变了皮肤的微环境，导致不同的单核细胞（MO） 正常和紫外线的行为。 UV MILIEU促进MO-MACROPHAGE（MPH） 并抑制树突状细胞（DC）抗原呈递细胞（APC）成熟。紫外线引起的 免疫抑制与皮肤中的补体成分IC3B沉积有关，并且 免疫抑制的逆转发生在用CD1 LB抗体处理的小鼠中（IC3B受体 在免疫抑制MO APC上，在用SCRL处理的小鼠中（防止IC3B形成）。莫 暴露于IC3B模型的体内情况；它们被诱导表达MO/MPH功能，并且 在DC开发中被捕，但保留了DC前体的潜力。最近的数据表明p38 MAP激酶信号通路参与DC成熟，由ERK MAP激酶平衡， 抗体的CD1 LB参与激活ERK。因此，这很有趣 MAPK信号通路引起的transcipt的初步数据非常重要 IC3B单核细胞CD1 lb的互动后上调。也非常显着上调 是OnCostatin M/IL-6家族受体/SOCS3信号通路，可以优先 通过DC促进MPH，并与ERK相互作用。因此，要检验的假设是 这些信号通路是否代表IC3B介导MO的关键机制 分化，最终是紫外线诱导的免疫抑制。 AIM我检查MAPK激活 并利用化学和主导的负面MAPK抑制剂和MAPK过表达策略 确定IC3B是否在MO分化过程中批判性地改变了p38/ERK信号的平衡。目的 II测试SOCS3/IL6受体家族信号级联是否与 IC3B对DC和MPH的Mo前体修改的机制以及MAPK的链接 路径。 AIM III在体内翻译了这些发现，以确认其在综合免疫中的作用 反应调节，导致具有临床影响的新型免疫治疗策略。