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 synt hesize proinflammatory leukotrienes (LTs). Regulation of 5-LO and FLAP expression is a major determinant of cellular LT synthesis. We examin ed the effects of proinflammatory [interleukin (IL)-1 and interferon ( IFN)-gamma 1 and T helper lymphocyte subset 2 (TH-2; IL-4 and IL-13) c ytokines on (1) LTB4 production, and (2) 5-LO and FLAP expression in H PBMs. We show that IL-1 and IFN-gamma stimulate, whereas IL-4 and IL-1 3 inhibit ionophore-activated LTB4 release. The stimulatory effects of IL;1 and IFN-gamma were apparent at 16 to 36 hours of incubation. IL- l modestly increased FLAP mRNA and significantly increased 5-LO mRNA s teady state levels at 74 and 36 hours of incubation, respectively. IFN -gamma 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 d ecreased FLAP mRNA and protein steady state levels. These results demo nstrate that regulation of monocyte LTB4 biosynthesis by different cyt okines 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 subp opulations may modulate monocyte function in inflammation.