Temporal effect of tumor necrosis factor alpha on murine macrophages infected with Mycobacterium avium
Temporal effect of tumor necrosis factor alpha on murine macrophages infected with Mycobacterium avium
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DOI：
10.1128/iai.65.6.2100-2106.1997
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发表时间：
1997-06-01
影响因子：
3.1
通讯作者：
Emerson, CL
中科院分区：
文献类型：
--
作者：
Eriks, IS;Emerson, CL
禽分枝杆菌复合体的成员是一类在面对免疫反应时持续存在于巨噬细胞内的细菌，这些细菌的消除可能是由于细胞因子诱导的巨噬细胞的激活，因为肿瘤坏死因子α(TNFα)激活的巨噬细胞似乎对杀灭细胞内的鸟分支杆菌至关重要，因此早期下调感染的巨噬细胞中的肿瘤坏死因子-α水平被认为是禽分枝杆菌强毒株的生存机制。我们研究了肿瘤坏死因子-α与不同毒力的鸟分支杆菌菌株生长的关系，通过它们在小鼠骨髓来源的巨噬细胞中的生长能力来衡量。当加入外源性的肿瘤坏死因子-α，即可抑制巨噬细胞的感染，显著抑制强毒株的生长。如果肿瘤坏死因子-α的加入延迟24小时或更长时间，则生长抑制被取消。为了确定早期下调TNF-α水平是否可以解释强毒株和无毒株的不同生长，随着时间的推移，已被证明抑制未感染巨噬细胞产生TNF-α的TNF-α和前列腺素E-2(PGE(2))的水平被定量，而BG酶联免疫吸附试验测得的TNF-α和PGE(2)在感染后6h明显上调，表明禽类分支杆菌在巨噬细胞中复制的能力与早期下调TNF-α的产生没有直接关系。感染后立即用干扰素处理感染的巨噬细胞，可显著提高NO水平，但不影响强毒株的生长。这些结果表明，虽然在所有M.avium菌株的培养上清液中都存在显著水平的肿瘤坏死因子-α，但从强毒的M.avium菌株的培养上清液中生物活性的TNF-α水平显著降低。初步结果提示，可溶性肿瘤坏死因子受体上调可能是肿瘤坏死因子-α生物活性降低的机制之一。
Members of the Mycobacterium avium complex are a family of bacteria that persist within macrophages in the face of an immune response, Elimination of these organisms is likely due to cytokine-induced macrophage activation, Because macrophage activation by tumor necrosis factor alpha (TNF alpha) appears critical for killing of intracellular M. avium, early downregulation of TNF-alpha levels in infected macrophages has been suggested as a survival mechanism for virulent strains of M. avium. We examined the relationship between TNF-alpha and growth of M. avium strains of differing virulence, as measured by their ability to grow in murine bone marrow-derived macrophages. When exogenous TNF-alpha was added immediately fallowing macrophage infection, significant growth inhibition of virulent M. avium strains was observed. If TNF-alpha addition was delayed by 24 h or more, growth inhibition was abrogated. To determine if early downregulation of TNF-alpha levels could explain the differential growth of virulent and avirulent strains, levels of TNF-alpha and prostaglandin E-2 (PGE(2)), which has been shown to suppress TNF-alpha production in uninfected macrophages, were quantified over time, Upregulation of both TNF-alpha and PGE(2), as measured bg enzyme-linked immunosorbent assay, was evident by 6 h postinfection, indicating that the ability of M. avium to replicate in macrophages was not directly correlated with early downregulation of TNF-alpha production. However, TNF-alpha bioactivity, as measured by cytotoxicity, was significantly decreased in virulent M. avium strains at all time periods examined, Treatment of infected macrophages with gamma interferon immediately after infection resulted in significantly increased levels of nitric oxide but did not affect the growth of virulent M. avium strains. These results suggest that while significant levels of TNF-alpha are present in supernatants from all M. avium strains, levels of biologically active TNF-alpha are significantly reduced in supernatants from virulent M. avium strains. Preliminary results suggest that upregulation of the soluble p75 TNF receptor may be one mechanism by which TNF-alpha bioactivity reduction occurs.