The Mechanisms of Profibrotic Sensitization by IL33

IL33 促纤维化致敏的机制

• 批准号: 8863006
• 负责人: Sergei P. Atamas
• 金额: $ 38.38万
• 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/8863006
• 关键词: Address; Adverse effects; Affect; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Attenuated; Autoimmunity; Binding; Blast Cell; Bleomycin; Cause of Death; Cell Surface Receptors; Cell surface; Cells; Cessation of life; Chronic; Collagen; Data; Dermal; Deterioration; Development; 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; cytokine; design; in vivo; indium-bleomycin; 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（由申请人提供）：硬皮病肺病（SLD）是慢性肺部炎症和持续纤维化的组合，是系统性硬化症患者死亡的主要原因。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-β（TGF-β）作为中心促纤维化因子而突出，包括在SLD中，但它也是免疫抑制和抗炎主调节剂。因此，靶向TGF-β可能引起强烈的促炎宿主反应。避免这种不必要的、潜在有害的副作用在技术上具有挑战性。我们提出了一个概念上的新范例，建议的机制的基础上，如果得到证实，将允许以最小限度地影响其基础抗炎和免疫抑制作用的方式靶向促纤维化TGF-β通路。我们以前报道过，从SLD和相关疾病特发性肺纤维化患者中获得的成纤维细胞显示白细胞介素（IL）-33 mRNA和蛋白的表达升高;在博莱霉素纤维化模型中也发生了类似的升高，IL-33的基因递送增强了体内炎症和纤维化宿主对博莱霉素的反应。在成纤维细胞培养物中，IL-33强烈上调Smad 2/3磷酸化，这似乎不依赖于TGF-β，因为IL-33递送不增加TGF-β、TGF-β活化的、含α V的整联蛋白或胶原mRNA和蛋白的表达，并且阻断性抗TGF-β抗体不能减弱IL-33对Smad 2/3磷酸化的作用。此外，当与TGF-β刺激成纤维细胞组合时，IL-33增强胶原蛋白生物合成的程度远大于预期的累加效应。因此，数据表明IL-33表达增强TGF-β的促纤维化作用，但不通过TGF-β起作用。我们假设IL-33通过诱导纤维化偏向信号增强TGF-β的促纤维化作用，并且本提议的目的是研究相应的分子机制。1）确定IL-33是否通过其特异性细胞表面受体T1/ST 2诱导细胞内信号传导，或者通过直接结合TGF β R和/或下游细胞内信号传导分子，来增强促纤维化TGF β R调节; 2）描述由IL-33偏向胶原蛋白产生和一系列促纤维化细胞因子表达的经典和非经典TGF-β信号传导途径组分;和 减少博来霉素和TGF-β引起的体内组织纤维化。如果该研究的假设得到验证，则结果将形成I-33-TGF-β纤维化偏向途径的未来分子靶向的基础，同时保留有益的抗炎TGF-β驱动的调节，从而导致设计用于SLD和其他组织纤维化中的纤维化的新疗法的概念转变。