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Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3897-3905
Granulocyte-Macrophage Colony-Stimulating Factor Upregulates Reduced
5-Lipoxygenase Metabolism in Peripheral Blood Monocytes and
Neutrophils in Acquired Immunodeficiency Syndrome
Michael J. Coffey,
Susan M. Phare,
Sandro Cinti,
Marc Peters-Golden, and
Powel H. Kazanjian
From the Divisions of Pulmonary and Critical Care Medicine and
Infectious Diseases, University of Michigan Medical Center, Ann Arbor,
MI.
Leukotrienes (LT) are mediators derived from the 5-lipoxygenase
(5-LO) pathway, which play a role in host defense, and are synthesized
by both monocytes (peripheral blood monocyte [PBM]) and neutrophils
(PMN). Because 5-LO metabolism is reduced in alveolar macrophages and
PMN from acquired immunodeficiency syndrome (AIDS) subjects, we
investigated the synthesis of LT by PBM and PMN from these subjects.
There was a reduction (74.2% ± 8.8% of control) in LT synthesis in
PBM from human immunodeficiency virus (HIV)-infected compared with
normal subjects. Expression of 5-LO (51.2% ± 8.8% of control), and
5-LO activating protein (FLAP) (48.5% ± 8.0% of control) was
reduced in parallel. We hypothesized that this reduction in LT
synthetic capacity in PBM and PMN was due to reduced cytokine
production by CD4 T cells, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We treated 10 AIDS subjects with
GM-CSF for 5 days. PBM 5-LO metabolism ex vivo was selectively increased after GM-CSF therapy and was associated with increased 5-LO
and FLAP expression. PMN leukotriene B4
(LTB4) synthesis was also augmented and
associated with increased 5-LO, FLAP, and cytosolic phospholipase
A2 expression. In conclusion, as previously demonstrated for PMN, PBM from AIDS subjects also demonstrate reduced
5-LO metabolism. GM-CSF therapy reversed this defect in both PBM and
PMN. In view of the role of LT in antimicrobial function, cytokine
administration in AIDS may play a role as adjunct therapy for infections.
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