Granulocyte colony-stimulating factor administration to HIV-infected subjects augments reduced leukotriene synthesis and anticryptococcal activity in neutrophils.

Abstract

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 Ϯ 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 Ϯ 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 g daily for 5 d) on eight HIV-infected subjects. PMN were studied in vitro before therapy (day 1) and on days 4 and 7. LTB 4 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. ( J. Clin. Invest. 1998. 102:663-670.)

Leukotriene B4 Triggers the In Vitro and In Vivo Release of Potent Antimicrobial Agents

“…Whether LTB 4 could be a useful immunostimulant for the treatment of infectious diseases remains to be investigated in clinical trials; numerous animal studies have already reported a beneficial effect of this eicosanoid models of infection (57)(58)(59)(60)(61)(62)(63)(64). LTB 4 administration to humans has been documented (29,65,66), with pharmacodynamic effects (␣-defensin and MIP-1␤ release (29) and PMN count variations (our unpublished data)) similar to what is reported in this study in monkeys without significant adverse events.…”

“…Furthermore, peripheral blood PMN (58,69), monocytes (70), and alveolar macrophages (71) from HIV-1-infected subjects have a profound defect in their capacity to produce leukotrienes. This deficit translates into the improper in vitro killing of microbes but can be overcome by G-CSF administration to HIV-1-infected subjects and the concomitant restoration of leukotriene biosynthesis potential (58).…”

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

“…In addition to their originally recognized roles in myelopoiesis, G-CSF and GM-CSF are also recognized to up-regulate leukocyte functional responses, such as the recruitment, survival, phagocytosis, and microbicidal activities of neutrophils, monocytes, and macrophages (63). A role in LT synthesis is demonstrated by the facts that macrophages from GM-CSF-deficient mice exhibit reduced LT synthesis (64), and exogenous addition of CSFs has been shown to enhance the capacity for LT biosynthesis in vitro (65,66) and in vivo (49,67). Nitric oxide.…”

“…HIV infection. Peripheral blood neutrophils (49,78), monocytes (67), and alveolar macrophages (79) from patients with HIV infection have all been reported to manifest a profound defect in their capacity for stimulated LT generation. This defect was confined to the 5-LO pathway and was associated with reduced expression of 5-LO and FLAP.…”

“…In neutrophils, these effects were paralleled by increased capacity to kill fungi. That the augmented microbicidal activity was due to the increment in LT synthesis was indicated by the fact that it was completely abrogated by inclusion of a LT synthesis inhibitor (49). An early report noted that Pneumocystis pneumonia in patients with HIV infection was associated with less lung neutrophilia than observed in patients with this infection and other states of immunosuppression (81), and it is possible that the blunted neutrophil accumulation in HIV-infected individuals relates to this alveolar macrophage defect in LTB 4 biosynthesis.…”