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.

项目概要/摘要白细胞介素 38 (IL-38) 是 IL-1 家族的成员，尽管它被发现，但直到最近才对其进行研究 20年前。它是一种被忽视的细胞因子，因为尚未确定 IL-38 功能的受体。然而，在 2012 年，我们报道了重组人 IL-38 与 IL-36 受体（现为 IL-1R6）结合，并且抑制IL-17和IL-22的产生。在那项研究中，我们提出 IL-38 作为受体 IL-1R6 拮抗剂。然而，IL-38 的剂量反应并不是作为受体拮抗剂，而是作为受体拮抗剂。作为细胞活性的抑制剂。新数据表明 IL-38 需要 IL-1R6，这是一种孤儿受体 IL-1 家族，抑制 IL-17。 IL-1R9 以前称为 IL-1 受体相关蛋白样 1，将更名为研究了其在重组 IL-38 抑制先天免疫中的推定作用。使用 CRISPR/Cas 通过这些方法，我们培育了一群缺乏 IL-38 的小鼠。这些小鼠用于确定人类炎症性疾病小鼠模型对内源性 IL-38 的需求。在那些模型中如果 IL-38 缺陷小鼠的疾病严重程度恶化，我们将使用重组 IL-38 来治疗小鼠抑制先天性炎症。为了充分了解IL-38在先天免疫中的作用，我们产生了一个缺乏 IL-1R9 的小鼠群体。我们将研究 IL-1R9 功能的需要 IL-38 治疗可显着减少疾病的小鼠模型中的重组 IL-38 严重程度。该应用的一个独特之处是 IL-1R9 位于 X 染色体上，这是一个不寻常的发现细胞因子生物学。由于 IL-1R9 位于 X 染色体上，因此我们可以解决如何抑制先天性与女性相比，男性的免疫力受到影响。大多数自身免疫性疾病的发病率高达 70% 女性偏爱，每种自身免疫性疾病都会导致炎症，我们有设计了比较纯合 IL-1R9 缺陷男性与纯合 IL-1R9 女性的研究。在这些研究中，我们还将评估 IL-38 抑制 NLRP3 炎症小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 AIM 1 和 AIM 2 研究之外关于重组 IL-38 对先天免疫的抑制和 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 融合蛋白的基本原理是提供 IL-38 疗法的临床前数据。在 AIM 4 中，我们解决了细胞中 IL-38 释放的问题。 IL-38 在健康受试者中循环，但在有心血管事件风险的受试者中水平明显较低。然而，IL-38 是 B 细胞产物，表明 IL-38 前体的加工和从 B 细胞中的释放细胞不通过传统途径。我们将检查其他成员使用的分泌途径 IL-1 家族的功能：抑制 NLRP3 和抑制钙蛋白酶。这些研究的总体目标是推进 IL-38 的生物学和临床意义，并利用其抗炎特性 IL-38 作为治疗剂。

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）

IL-37 inhibits inflammasome activation and disease severity in murine aspergillosis.

DOI：
10.1371/journal.ppat.1004462
发表时间：
2014-11
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Moretti S;Bozza S;Oikonomou V;Renga G;Casagrande A;Iannitti RG;Puccetti M;Garlanda C;Kim S;Li S;van de Veerdonk FL;Dinarello CA;Romani L
通讯作者：
Romani L

Impact of rare and common genetic variation in the interleukin-1 pathway on human cytokine responses.

DOI：
10.1186/s13073-021-00907-w
发表时间：
2021-05-25
期刊：
Genome medicine
影响因子：
12.3
作者：
van Deuren RC;Arts P;Cavalli G;Jaeger M;Steehouwer M;van de Vorst M;Gilissen C;Joosten LAB;Dinarello CA;Mhlanga MM;Kumar V;Netea MG;van de Veerdonk FL;Hoischen A
通讯作者：
Hoischen A

Transcription, not synthesis, of interleukin-1 and tumor necrosis factor by complement.

补体对白细胞介素 1 和肿瘤坏死因子进行转录，而非合成。

DOI：
10.1038/ki.1990.12
发表时间：
1990
期刊：
Kidney international
影响因子：
19.6
作者：
Schindler,R;Lonnemann,G;Shaldon,S;Koch,KM;Dinarello,CA
通讯作者：
Dinarello,CA

Chlamydia pneumoniae stimulates IFN-gamma synthesis through MyD88-dependent, TLR2- and TLR4-independent induction of IL-18 release.

肺炎衣原体通过 MyD88 依赖性、TLR2 和 TLR4 独立诱导 IL-18 释放来刺激 IFN-γ 合成。

DOI：
10.4049/jimmunol.173.2.1477
发表时间：
2004
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Netea,MihaiG;Kullberg,BartJan;Jacobs,LiesbethEH;Verver-Jansen,TreesJG;vanderVen-Jongekrijg,Johanna;Galama,JochemMD;Stalenhoef,AntonFH;Dinarello,CharlesA;VanderMeer,JosWM
通讯作者：
VanderMeer,JosWM

The biology of interleukin-1.

IL-1 的生物学。