The Mechanisms of Profibrotic Sensitization by IL33

IL33 促纤维化致敏的机制

• 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
• 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

 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(申请人提供)：硬皮病肺部疾病(SLD)，一种慢性肺部炎症和顽固性纤维化的组合，是系统性硬化症患者的主要死亡原因。尽管我们对SLD的机制越来越了解，但仍需要更好的治疗方法。转化生长因子是包括系统性红斑狼疮在内的中枢促纤维化因子，但它也是免疫抑制和抗炎的主要调节因子。因此，以转化生长因子为靶点可能会引发强烈的促炎宿主反应。避免这种不必要的、潜在的有害副作用在技术上是具有挑战性的。我们提出了一个概念上的新范式，基于一个建议的机制，如果得到证实，将允许以一种最小程度影响其基本抗炎和免疫抑制作用的方式靶向促纤维化的转化生长因子途径。我们之前曾报道，从SLD和相关疾病特发性肺纤维化患者身上获得的成纤维细胞显示出IL-33mRNA和蛋白的高表达；在博莱霉素的纤维化模型中也出现了类似的升高，IL-33的基因传递增强了体内对博莱霉素的炎症和纤维化宿主反应。在成纤维细胞培养中，IL-33强烈上调Smad2/3的磷酸化，这似乎不依赖于转化生长因子，因为IL-33的传递不增加转化生长因子β、转化生长因子-β激活、含AV的整合素或胶原的mRNAs和蛋白的表达，并且阻断的抗转化生长因子抗体不能减弱IL-33对Smad2/3磷酸化的影响。此外，当与成纤维细胞的转化生长因子刺激相结合时，IL-33对胶原的生物合成的促进程度远远超过了相加效应的预期。因此，数据表明，IL-33的表达增强了转化生长因子-B的促纤维化作用，但不是通过转化生长因子-β起作用的。我们假设IL-33通过诱导偏向纤维化的信号转导而增强了转化生长因子的促纤维化作用，本研究的目的是探讨相应的分子机制。以下具体目标将基于已知的由IL-33和转化生长因子β控制的分子过程来探讨其机制的可能性：1)确定IL-33是通过其特定的细胞表面受体T1/ST2诱导细胞内信号传递，还是通过直接结合TGFBR和/或下游细胞内信号分子来加强促纤维化的转化生长因子的调节；2)描绘由IL-33偏向胶原产生和一系列促纤维化细胞因子表达的典型和非典型转化生长因子信号通路成分；以及3)确定是否全局和/或成纤维细胞特异性缺失IL-33 减少博莱霉素和转化生长因子引起的体内组织纤维化。如果这项研究的假设得到证实，研究结果将形成未来分子靶向I-33-转化生长因子-β纤维化偏向通路的基础，同时避免有益的抗炎转化生长因子驱动的调节，导致设计治疗系统性红斑狼疮和其他组织纤维化的新疗法的概念转变。