The Mechanisms of Profibrotic Sensitization by IL33

IL33 促纤维化致敏的机制

基本信息

批准号：
9247798
负责人：
Sergei P. Atamas
金额：
$ 34.54万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247798
关键词：
Address Adverse effects Affect Anabolism Anti-Inflammatory Agents Anti-inflammatory Antibodies Attenuated Autoimmunity Binding Bleomycin Cause of Death Cell Surface Receptors Cell surface Cells Cessation of life Chronic Collagen Data Dermal Deterioration Disease Disease Progression Extracellular Matrix Fibroblasts Fibrosis Future Gene Delivery Hamman-Rich syndrome Hematopoietic Immune response Immunosuppressive Agents Inflammation Inflammatory Integrins Interleukins Investigation Lead Life Lung Lung diseases MAPK3 gene Mediating Messenger RNA Modeling Molecular Molecular Target Pathology Pathway interactions Patients Phosphorylation Physiological Play Process Production Proteins Pulmonary Hypertension Pulmonary Inflammation Regulation Reporting Research Respiratory physiology Risk Role Scleroderma Series Signal Pathway Signal Transduction Signaling Molecule Systemic Scleroderma Tissues Transforming Growth Factor beta Transforming Growth Factors Triad Acrylic Resin Validation attenuation base course development cytokine design in vivo indium-bleomycin novel therapeutics prevent public health relevance receptor ward

项目摘要

DESCRIPTION (provided by applicant): Scleroderma lung disease (SLD), a combination of chronic pulmonary inflammation and unrelenting fibrosis, is the leading cause of death in patients with systemic sclerosis. Despite our increasing understanding of the mechanisms of SLD, better therapies are required. Transforming growth factor-ß (TGF-ß) stands out as the central profibrotic factor, including in SLD, but it is also the immunosuppressive and anti-inflammatory master regulator. Targeting TGF-ß might therefore provoke a robust proinflammatory host response. Avoiding this unwanted, potentially deleterious side effect is technically challenging. We propose a conceptually new paradigm based on a suggested mechanism that, if confirmed, would allow for targeting the profibrotic TGF-ß pathway in a way that minimally affects its basal anti-inflammatory and immunosuppressive action. We previously reported that fibroblasts obtained from patients with SLD and a related disease, idiopathic pulmonary fibrosis, display elevated expression of interleukin (IL)-33 mRNA and protein; similar elevations occur in the bleomycin model of fibrosis, and gene delivery of IL-33 potentiates the in vivo inflammatory and fibrotic host responses to bleomycin. In fibroblast culture, IL-33 strongly upregulates Smad2/3 phosphorylation, which appears to be independent of TGF-ß, because IL-33 delivery does not increase expression of TGF-ß, TGF-ß-activating, aV-containing integrins, or collagen mRNAs and proteins, and a blocking anti-TGF-ß antibody fails to attenuate the effect of IL-33 on Smad2/3 phosphorylation. Furthermore, when combined with TGF-ß stimulation of fibroblasts, IL-33 potentiates collagen biosynthesis to a far greater degree than would be anticipated for an additive effect. Thus, data suggest that IL-33 expression potentiates the profibrotic effect of TGF-ß but does not act through TGF-ß. We hypothesize that IL-33 potentiates the profibrotic effect of TGF-ß by inducing fibrosis-biased signaling, and the objective of this proposal is to investigate the corresponding molecular mechanisms. The following specific aims will address the mechanistic possibilities based on the known molecular processes controlled by IL-33 and TGF-ß: 1) Determine whether IL-33 potentiates profibrotic TGF-ß regulation by inducing intracellular signaling through its specific cell-surface receptor, T1/ST2, or, alternatively, through direct binding to the TGFBR and/or downstream intracellular signaling molecules; 2) Delineate the canonical and non-canonical TGF-ß signaling pathway components biased by IL-33 towards collagen production and expression of a spectrum of profibrotic cytokines; and 3) Establish whether global and/or fibroblast-specific deletion of IL-33 diminishes bleomycin- and TGF-ß-provoked tissue fibrosis in vivo. If the hypothesis of this investigation is validated, the results will form the basis for future molecular targeting of the I-33-TGF-ß fibrosis-biased pathway while sparing beneficial anti-inflammatory TGF-ß-driven regulation, leading to a conceptual shift in designing new therapies for fibrosis in SLD and other tissue fibroses.

描述（由应用提供）：硬皮病肺疾病（SLD）是慢性肺部感染和无屈服纤维化的组合，是全身性硬化症患者死亡的主要原因。尽管我们对SLD机制的理解越来越多，但仍需要更好的疗法。转化生长因子-ß（TGF-ß）是中心纤维化因子，包括在SLD中，但它也是靶向TGF-ß的免疫抑制和抗炎主tgf-ß可能会引起强大的促炎宿主反应。避免这种不必要的，潜在的有害副作用在技术上挑战。我们根据建议的机制提出了一种概念上的新范式，如果确认，该机制将允许以最小化其基本的抗炎和免疫抑制作用的方式来靶向纤维化的TGF-β途径。我们先前报道说，从SLD患者和相关疾病，特发性肺纤维化，白介素（IL）-33 mRNA和蛋白质表达升高的成纤维细胞表现出升高。在纤维化博来霉素模型中也发生了类似的升高，IL-33的基因递送了体内炎症和纤维化宿主对博来霉素的反应。在成纤维细胞培养中，IL-33强烈上调SMAD2/3磷酸化，这似乎与TGF-ß无关，因为IL-33的递送不会增加TGF-ß的表达Smad2/3磷酸化。此外，当与成纤维细胞的TGF-β刺激结合使用时，IL-33电位胶原蛋白生物合成的程度远大于预期的额外效果。这是数据表明，IL-33表达可能会产生TGF-ß的纤维化作用，但不通过TGF-ß起作用。我们假设IL-33通过诱导纤维化偏见的信号传导对TGF-ß的纤维化作用有可能，该建议的目的是研究相应的分子机制。 The following specific aims will address the mechanical possibilities based on the known molecular processes controlled by IL-33 and TGF-ß: 1) Determine Whether IL-33 potentials profibrotic TGF-ß regulation by induced intracellular signaling through its specific cell-surface receptor, T1/ST2, or, alternatively, through direct binding to the TGFBR and/or downstream intracellular signaling molecules; 2）描绘出由IL-33偏向胶原蛋白产生和表达的纯纤维化细胞因子的表达的规范和非传统TGF-ß信号通路成分； 3）确定IL-33的全球和/或成纤维细胞特定的缺失减少体内博来霉素和TGF-ß发动的组织纤维化。如果对该研究的假设进行了验证，则结果将构成I-33-TGF-β纤维化偏置途径的未来分子靶向的基础，同时保留有益的抗炎TGF-β驱动调节，从而导致在SLD和其他组织纤维纤维中设计新疗法的概念转移。