IL-4 Potentiates T Cell Death in Autoimmune Arthritis

IL-4 增强自身免疫性关节炎中的 T 细胞死亡

• 批准号: 6792202
• 负责人: JIAN ZHANG
• 金额: $ 9.72万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6792202
• 关键词: SCID mouse; T cell receptor; antigen receptors; arthritis; autoimmune disorder; cell cycle; cell death; clinical research; enzyme linked immunosorbent assay; flow cytometry; genetically modified animals; helper T lymphocyte; human tissue; immune tolerance /unresponsiveness; interferon gamma; interleukin 4; laboratory mouse; polymerase chain reaction; proteoglycan; receptor expression; western blottings

DESCRIPTION (provided by applicant): Activation-induced cell death (AICD) in T cells is one of the major mechanisms for peripheral tolerance. Repeated stimulation of T cells via their antigen receptor (TCR) induces coexpression of Fas and Fas ligand (FasL) on the surface of T cells and the FasL interaction leads to the "suicide" or "fratricide" of T cells. Proteoglycan (PG) induced arthritis (PGIA) is a novel autoimmune murine model induced by systemic immunization of BALB/c mice with cartilage PG. The development of the disease is based upon cross-reactive immune responses between the immunizing human and mouse (self) cartilage PGs in genetically susceptible BALB/c mice. In this autoimmune arthritis model, an aberrant proliferation of peripheral CD4+ T cells in vitro in response to TCR stimulation is found to be associated with low levels of AICD and a high ratio of interferon-gamma to interleukin-4 (IL-4) in arthritic mice. Moreover, the incidence and severity of PGIA is augmented in IL-4-deficient mice in comparison to wild-type (WT) BALB/c mice, whereas administration of IL-4 to WT BALB/c mice significantly reduces disease. Recent studies indicate that IL-4 can promote AICD by down regulating expression of Fas-associated death domain-like IL1 beta-converting enzyme inhibitory protein (FLIP) and up regulating FasL expression, and these effects are achieved via the up regulation of T cell sensitivity to IL-2. These findings together suggest that T helper 1 (Thl) cells from arthritic mice may be resistant to AICD which may be ascribed to a higher level of FLIP expression. The overall hypothesis of this research proposal is that IL-4 may potentiate peripheral deletion of autoreactive Thl cells in PGIA. The absence of IL-4 may facilitate the accumulation of autoreactive Thl cells in the periphery, leading to the breakdown of self-tolerance, and provoking inflammation in synovial joints by an antigen-driven mechanism. In this research proposal, studies are described to investigate whether and how IL-4 affects AICD of CD4+ T cells in PGIA. Specifically, they will determine whether (i) lack of IL4 results in a severely impaired Fas-mediated AICD of CD4+ T cells in IL-4deficient mice with PGIA; (ii) defective AICD of CD4 T cells in IL-4-deficient mice with PGIA is regulated by an aberrant expression of FLIP and/or FasL; (iii) IL-4-mediated Janus kianses/signal transducer and activator of transcription-6 signaling pathway confers the susceptibility of autoreactive T cells to AICD in PGIA; and (iv) IL-4 regulates the susceptibility of autoreactive T cells to AICD by adjusting the cell cycle progression.

描述（由申请人提供）：