Granulocyte-macrophage colony-stimulating factor upregulates reduced 5-lipoxygenase metabolism in peripheral blood monocytes and neutrophils in acquired immunodeficiency syndrome

Leukotrienes (LT) are mediators derived from the 5-lipoxygenase (5-LO) path way, which play a role in host defense, and are synthesized by both monocyt es (peripheral blood monocyte [PBM]) and neutrophils (PMN). Because 5-LO me tabolism is reduced in alveolar macrophages and PMN from acquired immunodef iciency syndrome (AIDS) subjects, we investigated the synthesis of LT by PB M and PMN from these subjects. There was a reduction (74.2% +/- 8.8% of con trol) in LT synthesis in PBM from human immunodeficiency virus (HIV)-infect ed compared with normal subjects. Expression of 5-LO (51.2% +/- 8.8% of con trol), and 5-LO activating protein (FLAP) (48.5% +/- 8.0% of control) was r educed in parallel. We hypothesized that this reduction in LT synthetic cap acity in PBM and PMN was due to reduced cytokine production by CD4 T cells, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We trea ted 10 AIDS subjects with GM CSF for 5 days. PBM 5-LO metabolism ex vivo wa s selectively increased after GM-CSF therapy and was associated with increa sed 5-LO and FLAP expression. PMN leukotriene B-4 (LTB4) synthesis was also augmented and associated with increased 5-LO, FLAP, and cytosolic phosphol ipase A(2) expression. In conclusion, as previously demonstrated for PMN. P BM from AIDS subjects also demonstrate reduced 5-LO metabolism. GM-CSF ther apy 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. (C) 1999 by The American Society of Hematol ogy.