Granulocyte colony-stimulating factor administration to HIV-infected subjects augments reduced leukotriene synthesis and anticryptococcal activity in neutrophils.
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.
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA. mcoffey@umich.edu
M J
MJ
Coffey
S M
SM
Phare
S
S
George
M
M
Peters-Golden
P H
PH
Kazanjian
D058927:5-Lipoxygenase-Activating Proteins; D017088:AIDS-Related Opportunistic Infections / Q000517:prevention & control; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis; D016718:Arachidonic Acid / Q000378:metabolism; D002352:Carrier Proteins; D003455:Cryptococcus neoformans / Q000276:immunology*; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007975:Leukotriene B4 / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis*; D008565:Membrane Proteins; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D011446:Prospective Studies
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D015289:Leukotrienes; D008565:Membrane Proteins; D016179:Granulocyte Colony-Stimulating Factor; D007975:Leukotriene B4; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase