Pathogenesis of Fever in Man

人类发烧的发病机制

基本信息

批准号：
10684033
负责人：
Charles anthony Dinarello
金额：
$ 35.28万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-12-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684033
关键词：
Address Affect Age Aging Agonist Alanine Anti-Inflammatory Agents Antibodies Aorta Autoimmune Diseases B-Lymphocytes Binding Biological Biology CRISPR/Cas technology Calpain Cardiovascular system Cells Chimeric Proteins Colitis Consensus Sequence Data Development Disease Disease model Dose Event Exhibits Family Fc Immunoglobulins Fc domain Female Fever Genetic Polymorphism Goals Grant High Fat Diet Homeostasis Human IL17 gene IL18 gene IgG1 Immunoglobulin G In Vitro Incidence Infection Inflammasome Inflammation Inflammatory Inflammatory Response Interleukin Receptor Interleukin-1 Interleukin-1 Receptors Interleukins Lesion Leucine Ligands Link Location Macrophage Medical Modeling Mouse Protein Mouse Strains Mus Myeloid Cells Natural Immunity Obesity Oral Orphan Pathogenesis Pathway interactions Patients Peptide Signal Sequences Production Property Proteins Recombinant Interleukins Recombinants Reporting Research Research Design Risk Role Schedule Severity of illness Signal Transduction Site Testing Therapeutic Therapeutic Uses Wild Type Mouse Woman X Chromosome antagonist aortic valve aortic valve disorder calcification clinically significant cytokine dextran sulfate sodium induced colitis disorder risk experimental study human data human disease human male human model in vivo inhibitor interleukin-22 male man member monocyte monomer mouse model neglect pre-clinical prevent receptor response

项目摘要

Project Summary/Abstract Interleukin-38 (IL-38), a member of the IL-1 family, has not been studied until recently despite its discovery 20 years ago. It is a neglected cytokine because no receptor was identified for how IL-38 functioned. However, in 2012, we reported that recombinant human IL-38 bound to the IL-36 receptor (now IL-1R6) and suppressed the production of IL-17 and IL-22. In that study, we proposed that IL-38 acted as a receptor antagonist for IL-1R6. However, the dose-response of IL-38 did not behave as receptor antagonist but rather acted as an inhibitor of cell activities. New data suggests that IL-38 requires IL-1R6, an orphan receptor in the IL-1 Family, to suppress IL-17. Formerly termed IL-1 Receptor Associated Protein Like-1, IL-1R9 will be studied for its putative role in the suppression of innate immunity by recombinant IL-38. Using CRISPR/Cas methods, we have generated a colony of mice that are deficient in IL-38. These mice are used to determine a requirement for endogenous IL-38 in mouse models of human inflammatory diseases. In those models where disease severity worsens in IL-38 deficient mice, we will use recombinant IL-38 to treat mice for suppression of innate inflammation. In order to fully understand the role of IL-38 in innate immunity, we generated a mouse colony deficient in IL-1R9. We will study the requirement of IL-1R9 for the function of recombinant IL-38 in those mouse models where treatment with IL-38 has significantly reduced disease severity. A unique aspect of this application is that IL-1R9 in on the X-chromosome, an unusual finding in cytokine biology. Because IL-1R9 is on the X-chromosome, we can address how suppression of innate immunity is affected in males compared to females. With most autoimmune diseases having a 70% predilection for females and with each autoimmune disease there is an inflammatory contribution, we have designed studies for comparisons of homozygous IL-1R9 deficient males to homozygous IL-1R9 females. In these studies, we will also evaluate the role of IL-38 to inhibit the activation of the NLRP3 inflammasome using a specific oral NLRP3 inhibitor presently used to treat patients. In addition to AIM 1 and AIM 2 studies on recombinant IL-38 suppression of innate immunity and the putative role of IL-1R9, we will produce and test an IL-38-Fc fusion protein (AIM 3). The rationale for producing an IL-38-Fc fusion protein is to provide pre-clinical data for an IL-38 therapeutic. In AIM 4 we address the issue of IL-38 release from the cell. IL-38 circulates in healthy subjects but levels are significantly low in subjects at risk for a cardiovascular events. However, IL-38 being a B-cell product suggests that processing of the IL-38 precursor and release from the cell is not via traditional pathways. We will examine pathways for secretion that are used by other members of the IL-1 Family : inhibition of NLRP3 and inhibition of calpains. The overall goal of these studies is to advance the biology and clinical significance of IL-38 as well as to exploit the anti-inflammatory properties of IL-38 as a therapeutic.

项目摘要/摘要 IL-1家族的成员Interleukin-38（IL-38）直到最近才研究 20年前。这是一种被忽视的细胞因子，因为没有发现IL-38的功能的受体。但是，在2012年，我们报道了与IL-36受体（现为IL-1R6）结合的重组人IL-38和抑制了IL-17和IL-22的产生。在这项研究中，我们提出IL-38充当受体 IL-1R6的拮抗剂。但是，IL-38的剂量反应并非作为受体拮抗剂，而是充当细胞活性的抑制剂。新数据表明IL-38需要IL-1R6，这是一个孤儿受体 IL-1家族，以抑制IL-17。以前称为IL-1受体相关蛋白（例如-1），IL-1R9将是研究了重组IL-38在抑制先天免疫中的推定作用。使用CRISPR/CAS 方法，我们产生了一个不足IL-38的小鼠菌落。这些小鼠用于确定在人类炎症性疾病的小鼠模型中内源性IL-38的需求。在这些模型中如果疾病严重程度在IL-38缺乏小鼠中恶化，我们将使用重组IL-38来治疗小鼠的小鼠抑制先天炎症。为了充分了解IL-38在先天免疫中的作用，我们产生了缺乏IL-1R9的小鼠菌落。我们将研究IL-1R9对功能的要求重组IL-38在那些用IL-38治疗的小鼠模型中显着降低了疾病严重程度。该应用程序的一个独特方面是IL-1R9在X-Cromosom体上，这是一个不寻常的发现细胞因子生物学。因为IL-1R9在X染色体上，我们可以解决先天的抑制与女性相比，男性的免疫力受到影响。大多数自身免疫性疾病患有70％女性的偏爱和每种自身免疫性疾病都有炎症性贡献，我们有设计的研究用于比较纯合IL-1R9缺乏雄性与纯合IL-1R9女性的研究。在这些研究中，我们还将评估IL-38在抑制NLRP3炎症体激活的作用使用目前用于治疗患者的特定口服NLRP3抑制剂。除了目标1和目标2研究关于重组IL-38抑制先天免疫和IL-1R9的假定作用，我们将生产和测试IL-38-FC融合蛋白（AIM 3）。产生IL-38-FC融合蛋白的理由是提供 IL-38治疗的临床前数据。在AIM 4中，我们解决了从单元中释放IL-38的问题。 IL-38 在健康受试者中循环，但心血管事件风险的受试者的水平明显低。但是，IL-38是B细胞产品，这表明处理IL-38前体并释放细胞不是通过传统途径。我们将检查其他成员使用的分泌途径 IL-1家族：抑制NLRP3和抑制calpains。这些研究的总体目标是提高IL-38的生物学和临床意义，并利用 IL-38作为治疗性。

项目成果

期刊论文数量（623）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Interleukin-1: amino acid sequences, multiple biological activities and comparison with tumor necrosis factor (cachectin).

DOI：
发表时间：
1986
期刊：
The Year in immunology
影响因子：
0
作者：
C. Dinarello
通讯作者：
C. Dinarello

Role of pro- and anti-inflammatory cytokines during inflammation: experimental and clinical findings.

DOI：
发表时间：
1997-07
期刊：
Journal of biological regulators and homeostatic agents
影响因子：
3.2
作者：
Dinarello Ca
通讯作者：
Dinarello Ca

Caspase-3-independent apoptotic pathways contribute to interleukin-32γ-mediated control of Mycobacterium tuberculosis infection in THP-1 cells.

DOI：
10.1186/s12866-015-0366-z
发表时间：
2015-02-21
期刊：
BMC microbiology
影响因子：
4.2
作者：
Bai X;Kinney WH;Su WL;Bai A;Ovrutsky AR;Honda JR;Netea MG;Henao-Tamayo M;Ordway DJ;Dinarello CA;Chan ED
通讯作者：
Chan ED

Human recombinant interleukin-38 suppresses inflammation in mouse models of local and systemic disease.

DOI：
10.1016/j.cyto.2020.155334
发表时间：
2021-01
期刊：
Cytokine
影响因子：
3.8
作者：
de Graaf DM;Maas RJA;Smeekens SP;Eisenmesser E;Redzic JS;Helsen MM;Powers NE;Li S;Kalabokis V;Gresnigt MS;Joosten LAB;Dinarello CA;van de Veerdonk FL
通讯作者：
van de Veerdonk FL

Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases.

通过在广泛的疾病中阻断白介素1来治疗炎症。