Prolonged toll-like receptor signaling by Mycobacterium tuberculosis and its 19-kilodalton lipoprotein inhibits gamma interferon-induced regulation of selected genes in macrophages
Prolonged toll-like receptor signaling by Mycobacterium tuberculosis and its 19-kilodalton lipoprotein inhibits gamma interferon-induced regulation of selected genes in macrophages
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DOI：
10.1128/iai.72.11.6603-6614.2004
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发表时间：
2004-11-01
影响因子：
3.1
通讯作者：
Harding, CV
中科院分区：
文献类型：
--
作者：
Pai, RK;Pennini, ME;Harding, CV
巨噬细胞感染结核分枝杆菌或暴露于结核分枝杆菌19 kDa脂蛋白16h可抑制干扰素诱导的主要组织相容性复合体II类(MHC-II)的表达，其机制涉及Toll样受体(TLRs)。结核分枝杆菌对干扰素-γ诱导的小鼠巨噬细胞MHC-II抗原(Ag)加工活性有抑制作用，但对白细胞介素4(IL-4)诱导的巨噬细胞MHC-II抗原(Ag)加工活性无影响，提示可抑制干扰素-γ诱导的基因调控。我们设计了一种方法来测试结核分枝杆菌感染细胞对干扰素-伽马的反应能力。为了建立结核分枝杆菌慢性感染伴随TLR信号延长的模型，将巨噬细胞感染结核分枝杆菌或在加入干扰素-γ前与结核分枝杆菌19 kDa脂蛋白孵育24 h。然后使用微阵列基因表达研究来确定结核分枝杆菌延长的TLR信号是否广泛地抑制了干扰素-伽马对巨噬细胞基因表达的调节。在347个干扰素-γ诱导的基因中，结核分枝杆菌和19-kDa脂蛋白分别抑制了42%和36%的诱导。用定量逆转录-聚合酶链式反应和流式细胞术检测了关键基因或基因产物，证实和推广了微阵列研究的结果。结核分枝杆菌抑制了干扰素-7对涉及MHC-II抗原加工、抗原呈递和T细胞招募的基因的诱导。这些作用在很大程度上依赖于髓系分化因子88，这意味着TLRs的作用。因此，结核分枝杆菌延长的TLR信号会抑制巨噬细胞对干扰素-γ的某些反应，特别是与MHC-II抗原呈递相关的反应。这种抑制可能促进结核分枝杆菌逃避T细胞反应和结核病感染的持久性。
Infection of macrophages with Mycobacterium tuberculosis or exposure to M. tuberculosis 19-kDa lipoprotein for >16 h inhibits gamma interferon (IFN-gamma) -induced major histocompatibility complex class II (MHC-II) expression by a mechanism involving Toll-like receptors (TLRs). M. tuberculosis was found to inhibit murine macrophage MHC-II antigen (Ag) processing activity induced by IFN-gamma but not by interleukin-4 (IL-4), suggesting inhibition of IFN-gamma-induced gene regulation. We designed an approach to test the ability of M. tuberculosis-infected cells to respond to IFN-gamma. To model chronic infection with M. tuberculosis with accompanying prolonged TLR signaling, macrophages were infected with M. tuberculosis or incubated with M. tuberculosis 19-kDa lipoprotein for 24 h prior to the addition of IFN-gamma. Microarray gene expression studies were then used to determine whether prolonged TLR signaling by M. tuberculosis broadly inhibits IFN-gamma regulation of macrophage gene expression. Of 347 IFN-gamma-induced genes, M. tuberculosis and 19-kDa lipoprotein inhibited induction of 42 and 36%, respectively. Key genes or gene products were also examined by quantitative reverse transcription-PCR and flow cytometry, confirming and extending the results obtained by microarray studies. M. tuberculosis inhibited IFN-7 induction of genes involved in MHC-II Ag processing, Ag presentation, and recruitment of T cells. These effects were largely dependent on myeloid differentiation factor 88, implying a role for TLRs. Thus, prolonged TLR signaling by M. tuberculosis inhibits certain macrophage responses to IFN-gamma, particularly those related to MHC-II Ag presentation. This inhibition may promote M. tuberculosis evasion of T-cell responses and persistence of infection in tuberculosis.