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

• Published in: The Journal of clinical investigation Vol. 102; no. 4; pp. 663 - 670
• Main Authors: Coffey, M J, Phare, S M, George, S, Peters-Golden, M, Kazanjian, P H
• Format: Journal Article
• Language: English
• Published: United States 15.08.1998
• Subjects: 5-Lipoxygenase-Activating Proteins; AIDS-Related Opportunistic Infections - prevention & control; Arachidonate 5-Lipoxygenase - biosynthesis; Arachidonic Acid - metabolism; Carrier Proteins; Cryptococcus; Cryptococcus neoformans - immunology; Granulocyte Colony-Stimulating Factor - therapeutic use; HIV Infections - drug therapy; Human immunodeficiency virus 1; Humans; Immunity, Cellular - drug effects; Leukotriene B4 - biosynthesis; Leukotrienes - biosynthesis; Membrane Proteins; Neutrophils - drug effects; Neutrophils - immunology; Prospective Studies
• ISSN: 0021-9738
• 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.