Contrasting effects of proinflammatory and T-helper lymphocyte subset-2 cytokines on the 5-lipoxygenase pathway in monocytes

Human peripheral blood monocytes (HPBMs) express 5-lipoxygenase (5-LO) and 5-LO activating protein (FLAP), and hence have an ability to synthesize proinflammatory leukotrienes (LTs). Regulation of 5-LO and FLAP expression is a major determinant of cellular LT synthesis. We examined the effects of proinflammatory [interleukin (IL)-1 and interferon (IFN)-γ] and T helper lymphocyte subset 2 (TH-2; IL-4 and IL-13) cytokines on (1) LTB4 production, and (2) 5-LO and FLAP expression in HPBMs. We show that IL-1 and IFN-γ stimulate, whereas IL-4 and IL-13 inhibit ionophore-activated LTB4 release. The stimulatory effects of IL-1 and IFN-γ were apparent at 16 to 36 hours of incubation. IL-1 modestly increased FLAP mRNA and significantly increased 5- LO mRNA steady state levels at 24 and 36 hours of incubation, respectively. IFN-γ did not change the mRNA or protein expression of either 5-LO or FLAP. The inhibitory effects of IL-4 and IL-13 were associated with decreased FLAP mRNA and protein steady state levels. These results demonstrate that regulation of monocyte LTB4 biosynthesis by different cytokines proceeds via different pathways that partly involve modulation of the expression of the key proteins. 5-LO and FLAP. In addition, the contrasting effects of proinflammatory and TH-2-derived cytokines on monocyte LTB4 production demonstrate mechanisms by which cytokine subpopulations may modulate monocyte function in inflammation.