Sengupta T K, Chen A, Zhong Z, Darnell J E, Ivashkiv L B
Department of Medicine, Hospital for Special Surgery, New York, New York 10021.
J Exp Med. 1995 Mar 1;181(3):1015-25. doi: 10.1084/jem.181.3.1015.
Activated monocytes play an important role in the pathogenesis of inflammatory arthritis. Blood monocytes which enter the inflamed joint become activated upon adherence to extracellular matrix and exposure to a complex inflammatory environment. We have analyzed the mechanism of monocyte activation by soluble factors present in inflammatory synovial fluid (SF). Greater than 75% of inflammatory SFs tested (a total of 22 fluids to date) increased cell surface expression and dramatically increased mRNA levels of monocyte activation markers Fc gamma RI, Fc gamma RIII, and HLA-DRA. This induction was not triggered by adherence, a known activating stimulus, and several lines of evidence showed that induction was not dependent upon interferon gamma (IFN-gamma). Induction was not prevented by neutralizing anti-IFN-gamma antibodies and IFN-gamma was not detected in the SFs using a sensitive enzyme-linked immunosorbent assay. The SFs also were not able to activate the IFN-gamma-activated transcription factor Stat1, thus providing further support for the absence of IFN-gamma. SFs did activate a related signal transducer and activator of transcription (STAT) family factor, termed Stat-SF, which bound specifically to the IFN-gamma response region (GRR), a well-characterized transcription element in the Fc gamma RI promoter. Based upon DNA-binding specificity and mobilities in gel shift assays, and reactivity with specific antisera, Stat-SF likely contains Stat3, or a closely related STAT family member. Neutralization of interleukin 6, a cytokine present in SFs which is known to activate Stat3, abolished the activation of Stat-SF and inhibited the induction of Fc gamma RI expression by SFs. These results demonstrate the activation of monocytes by inflammatory SF and suggest that monocyte activation at an inflammatory site may occur in the absence of IFN-gamma through the triggering of signal transduction pathways that activate STAT transcription factors.
活化的单核细胞在炎性关节炎的发病机制中起重要作用。进入发炎关节的血液单核细胞在黏附于细胞外基质并暴露于复杂的炎性环境后会被激活。我们分析了炎性滑液（SF）中可溶性因子激活单核细胞的机制。超过75%的测试炎性滑液（迄今为止共22份滑液）增加了细胞表面表达，并显著提高了单核细胞活化标志物FcγRI、FcγRIII和HLA-DRA的mRNA水平。这种诱导不是由黏附（一种已知的激活刺激）触发的，并且多项证据表明诱导不依赖于干扰素γ（IFN-γ）。中和抗IFN-γ抗体不能阻止诱导，并且使用灵敏的酶联免疫吸附测定法在滑液中未检测到IFN-γ。滑液也不能激活IFN-γ激活的转录因子Stat1，从而进一步支持了IFN-γ不存在的观点。滑液确实激活了一种相关的信号转导和转录激活因子（STAT）家族因子，称为Stat-SF，它特异性地结合到IFN-γ反应区域（GRR），这是FcγRI启动子中一个特征明确的转录元件。基于凝胶迁移试验中的DNA结合特异性和迁移率以及与特异性抗血清的反应性，Stat-SF可能包含Stat3或一个密切相关的STAT家族成员。中和白细胞介素6（一种存在于滑液中已知可激活Stat3的细胞因子）消除了Stat-SF的激活，并抑制了滑液对FcγRI表达的诱导。这些结果证明了炎性滑液对单核细胞的激活，并表明在炎性部位单核细胞的激活可能在没有IFN-γ的情况下通过激活STAT转录因子的信号转导途径的触发而发生。
