Zhang L, English D, Andersen B R
Department of Medicine and Microbiology/Immunology, University of Illinois, College of Medicine, Chicago.
J Immunol. 1991 Apr 15;146(8):2730-6.
The principal sulfatide of a group of acidic lipids from virulent Mycobacterium tuberculosis, sulfolipid-1 (SL-1), stimulates neutrophil superoxide (O2-) generation and, at lower concentrations, primes neutrophil response to several other metabolic agonists including FMLP, and PMA. These responses to SL-1 were examined in relation to diacylglycerol (DAG) generation, Ca2+ availability and activation of guanine nucleotide binding proteins to clarify the signal transduction pathways involved. Pertussis toxin inhibited the ability of SL-1 to both stimulate neutrophils directly and to prime neutrophils for subsequent responses induced by PMA, suggesting a role for one or more guanine nucleotide regulating proteins in both responses. SL-1 induced a rise in neutrophil DAG levels. DAG generation was inhibited by pretreatment of cells with pertussis toxin. Depletion of extracellular Ca2+ ablated O2- release induced by stimulatory levels of SL-1 but did not inhibit the priming effect induced by substimulatory concentrations of the lipid. Investigation of the activation of the neutrophil NADPH oxidase in a cell-free system revealed that the SL-1-priming effect was associated with translocation of the soluble cytosolic factors required for activation of the enzyme. Cytosolic factor translocation was not observed in pertussis toxin pretreated cells. Our results provide evidence for the role of a guanine nucleotide binding protein in both priming and direct activation of neutrophils by SL-1. This G protein regulates both SL-1-induced DAG generation and cytosolic cofactor translocation involved in neutrophil activation and priming. The multiplicity of effects of SL-1 on signal transduction pathways leading to phagocyte activation and priming may exert a profound influence on the pathogenicity of M. tuberculosis.
来自强毒力结核分枝杆菌的一组酸性脂质中的主要硫脂——硫脂-1（SL-1），可刺激中性粒细胞产生超氧化物（O2-），并且在较低浓度时，可使中性粒细胞对包括FMLP和佛波酯（PMA）在内的其他几种代谢激动剂产生反应。研究了这些对SL-1的反应与二酰基甘油（DAG）生成、Ca2+可用性以及鸟嘌呤核苷酸结合蛋白激活之间的关系，以阐明其中涉及的信号转导途径。百日咳毒素抑制了SL-1直接刺激中性粒细胞以及使中性粒细胞对随后由PMA诱导的反应产生致敏的能力，这表明一种或多种鸟嘌呤核苷酸调节蛋白在这两种反应中均发挥作用。SL-1可诱导中性粒细胞DAG水平升高。用百日咳毒素预处理细胞可抑制DAG的生成。细胞外Ca2+耗尽可消除由刺激水平的SL-1诱导的O2-释放，但不抑制由亚刺激浓度的该脂质诱导的致敏作用。在无细胞系统中对中性粒细胞NADPH氧化酶激活的研究表明，SL-1的致敏作用与该酶激活所需的可溶性胞质因子的转位有关。在百日咳毒素预处理的细胞中未观察到胞质因子转位。我们的结果为鸟嘌呤核苷酸结合蛋白在SL-1对中性粒细胞的致敏和直接激活中的作用提供了证据。这种G蛋白调节SL-1诱导的DAG生成以及参与中性粒细胞激活和致敏的胞质辅因子转位。SL-1对导致吞噬细胞激活和致敏的信号转导途径的多种作用可能对结核分枝杆菌的致病性产生深远影响。
