Kincaid Eleanor Z, Ernst Joel D
Biomedical Sciences Graduate Program and Division of Infectious Diseases, University of California, San Francisco, CA 94143, USA.
J Immunol. 2003 Aug 15;171(4):2042-9. doi: 10.4049/jimmunol.171.4.2042.
Mycobacterium tuberculosis is a highly successful human pathogen. A major component of this success is the pathogen's ability to avoid eradication by the innate and adaptive immune responses throughout the course of infection. IFN-gamma, a potent activator of the microbicidal activities of macrophages, is essential for control of M. tuberculosis infection, but is unable to stimulate macrophages to kill M. tuberculosis. We have found that infection of the human monocytic cell line, THP-1, resulted in reduced cellular responses to IFN-gamma, manifested as impaired induction of CD64 surface expression and transcription. This defect in transcription occurred despite normal activation of STAT1 in infected macrophages: there was no decrease in STAT1 tyrosine or serine phosphorylation, nuclear translocation, or binding of a minimal IFN-gamma response sequence. Assays of STAT1 function in M. tuberculosis-treated cells also revealed no defect in activation of a minimal gamma-activated sequence construct or STAT1 recruitment to and binding at the endogenous CD64 promoter. In addition, M. tuberculosis did not affect histone acetylation at the CD64 promoter. The inhibition of transcription was gene selective: while transcription of CD64 and class II transactivator were decreased, certain other IFN-gamma-responsive genes either were unaffected or were increased by M. tuberculosis. These results indicate that M. tuberculosis inhibits the response to IFN-gamma by a mechanism distinct from either suppressor of cytokine signaling-1 inhibition of STAT1 phosphorylation or protein inhibitor of activated STAT interference with DNA binding, and indicate that other mechanisms of inhibition of IFN-gamma responses remain to be discovered.
结核分枝杆菌是一种极其成功的人类病原体。这种成功的一个主要因素是该病原体在整个感染过程中能够避免被先天性和适应性免疫反应清除。干扰素-γ是巨噬细胞杀菌活性的有效激活剂，对控制结核分枝杆菌感染至关重要，但无法刺激巨噬细胞杀死结核分枝杆菌。我们发现，人类单核细胞系THP-1的感染导致细胞对干扰素-γ的反应降低，表现为CD64表面表达和转录的诱导受损。尽管感染的巨噬细胞中STAT1正常激活，但转录仍存在缺陷：STAT1酪氨酸或丝氨酸磷酸化、核转位或最小干扰素-γ反应序列的结合均未减少。对结核分枝杆菌处理的细胞中STAT1功能的检测还显示，最小γ-激活序列构建体的激活或STAT1向内源性CD64启动子的募集和结合均无缺陷。此外，结核分枝杆菌不影响CD64启动子处的组蛋白乙酰化。转录抑制具有基因选择性：虽然CD64和II类反式激活因子的转录减少，但某些其他干扰素-γ反应基因要么未受影响，要么被结核分枝杆菌增加。这些结果表明，结核分枝杆菌通过一种不同于细胞因子信号传导抑制因子-1对STAT1磷酸化的抑制或活化STAT蛋白抑制剂对DNA结合的干扰的机制来抑制对干扰素-γ的反应，并表明仍有待发现其他抑制干扰素-γ反应的机制。
