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.