Coffey M J, Phare S M, George S, Peters-Golden M, Kazanjian P H
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
J Clin Invest. 1998 Aug 15;102(4):663-70. doi: 10.1172/JCI2117.
Neutrophil (PMN) dysfunction occurs in HIV infection. Leukotrienes (LT) are mediators derived from the 5-lipoxygenase (5-LO) pathway that play a role in host defense and are synthesized by PMN. We investigated the synthesis of LT by PMN from HIV-infected subjects. There was a reduction (4.0+/-1.3% of control) in LT synthesis in PMN from HIV-infected compared with normal subjects. This was associated with reduced expression of 5-LO-activating protein (31.2+/-9.6% of normal), but not of 5-LO itself. Since HIV does not directly infect PMN, we considered that these effects were due to reduced release of cytokines, such as granulocyte colony-stimulating factor (G-CSF). We examined the effect of G-CSF treatment (300 microgram daily for 5 d) on eight HIV-infected subjects. PMN were studied in vitro before therapy (day 1) and on days 4 and 7. LTB4 synthesis was increased on day 4 of G-CSF treatment, and returned toward day 1 levels on day 7. 5-LO and 5-LO-activating protein expression were increased in parallel. As a functional correlate to this increase in PMN LT synthesis by G-CSF, we examined the effects on killing of Cryptococcus neoformans. Anticryptococcal activity of PMN from HIV-infected subjects was less than that of PMN from normal subjects. G-CSF treatment improved fungistatic activity of PMN. This increase in antifungal activity was attenuated by in vitro treatment with the LT synthesis inhibitor, MK-886. In conclusion, PMN from HIV-infected subjects demonstrate reduced 5-LO metabolism and antifungal activity in vitro, which was reversed by in vivo G-CSF therapy.
中性粒细胞（PMN）功能障碍在HIV感染中会出现。白三烯（LT）是源自5-脂氧合酶（5-LO）途径的介质，在宿主防御中发挥作用，由PMN合成。我们研究了HIV感染受试者的PMN对白三烯的合成情况。与正常受试者相比，HIV感染受试者的PMN中白三烯合成减少（为对照的4.0±1.3%）。这与5-LO激活蛋白表达降低（为正常的31.2±9.6%）有关，但与5-LO本身的表达无关。由于HIV不会直接感染PMN，我们认为这些影响是由于细胞因子（如粒细胞集落刺激因子（G-CSF））释放减少所致。我们检测了G-CSF治疗（每日300微克，共治疗5天）对8名HIV感染受试者的影响。在治疗前（第1天）以及第4天和第7天对PMN进行体外研究。在G-CSF治疗的第4天，白三烯B4（LTB4）合成增加，在第7天又回到第1天的水平。5-LO和5-LO激活蛋白的表达也相应增加。作为G-CSF使PMN白三烯合成增加的功能关联，我们检测了其对新型隐球菌杀伤作用的影响。HIV感染受试者的PMN的抗隐球菌活性低于正常受试者的PMN。G-CSF治疗改善了PMN的抑菌活性。这种抗真菌活性的增加被白三烯合成抑制剂MK-886的体外处理所减弱。总之，HIV感染受试者的PMN在体外表现出5-LO代谢和抗真菌活性降低，而体内G-CSF治疗可使其逆转。
