Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, Komiya S, Kosai K, Hanakawa Y, Hashimoto K, Nagata K, Yoshimura A
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
J Clin Invest. 2001 Dec;108(12):1781-8. doi: 10.1172/JCI13568.
Immune and inflammatory systems are controlled by multiple cytokines, including ILs and INFs. These cytokines exert their biological functions through Janus tyrosine kinases and STAT transcription factors. One such cytokine, IL-6, has been proposed to contribute to the development of rheumatoid arthritis (RA). We found that STAT3 was strongly tyrosine phosphorylated in synovial tissue of RA patients, but not those with osteoarthritis. Blockade of the IL-6-gp130-JAK-STAT3-signaling pathway might therefore be beneficial in the treatment of RA. We show here that the mRNA for the endogenous cytokine signaling repressor CIS3/SOCS3 is abundantly expressed in RA patients. To determine whether CIS3 is effective in treating experimental arthritis, a recombinant adenovirus carrying the CIS3 cDNA was injected periarticularly into the ankle joints of mice with antigen-induced arthritis or collagen-induced arthritis (CIA). Periarticular injection of CIS3 adenovirus drastically reduced the severity of arthritis and joint swelling compared with control groups. CIS3 was more effective than a dominant-negative form of STAT3 in the CIA model. Thus, induction of CIS3 could represent a new approach for effective treatment of RA.
免疫和炎症系统受多种细胞因子调控，包括白细胞介素（ILs）和干扰素（INFs）。这些细胞因子通过Janus酪氨酸激酶和信号转导及转录激活因子（STAT）转录因子发挥其生物学功能。一种这样的细胞因子，即白细胞介素-6（IL-6），已被认为与类风湿关节炎（RA）的发病有关。我们发现，在类风湿关节炎患者的滑膜组织中，信号转导及转录激活因子3（STAT3）有强烈的酪氨酸磷酸化，但骨关节炎患者的滑膜组织中则没有。因此，阻断IL-6-糖蛋白130（gp130）-Janus激酶（JAK）-STAT3信号通路可能对类风湿关节炎的治疗有益。我们在此表明，内源性细胞因子信号抑制因子CIS3/细胞因子信号转导抑制因子3（SOCS3）的信使核糖核酸（mRNA）在类风湿关节炎患者中大量表达。为了确定CIS3在治疗实验性关节炎方面是否有效，将携带CIS3互补脱氧核糖核酸（cDNA）的重组腺病毒关节周围注射到抗原诱导性关节炎或胶原诱导性关节炎（CIA）小鼠的踝关节。与对照组相比，关节周围注射CIS3腺病毒可显著减轻关节炎的严重程度和关节肿胀。在CIA模型中，CIS3比信号转导及转录激活因子3的显性阴性形式更有效。因此，诱导CIS3可能代表一种有效治疗类风湿关节炎的新方法。
