Interactions between lipoxin A4, the stable analogue 16-phenoxy-lipoxin A4 and leukotriene B4 in cytokine generation by human monocytes

Lipoxins display both stimulatory and inhibitory actions with leucocytes that are cell-type dependent. We tested whether lipoxin A(4) (LXA(4)) and its stable synthetic analogue 16-phenoxy-17-18,19,20-tetranor-lipoxin-A(4) (16-phe-LXA(4)) modulated the ability of human blood monocytes (MO) to express mRNA and proteins for interleukin-1beta (IL-1beta), IL-6 and IL-1 receptor antagonist (IL-1Ra) in vitro and compared their actions with lipopolysaccharide (LPS) and leukotriene B-4 (LTB4). 16-phe-LXA(4), LPS and LTB4, but not LXA(4), induced gene expression of IL-1beta in MO. IL-1beta protein synthesis increased by LPS (1500-fold), LTB4 (280-fold) and 16-phe-LXA(4) (30-fold). Although the IL-1Ra gene was constitutively activated, mRNA concentration not affected by any of the stimulants, IL-Ra protein synthesis was increased by LPS (with 74%), 16-phe-LXA(4) (35%) and LTB4 (20%), but not by LXA(4). Each of these stimuli upregulated the IL-6 gene. Increases of IL-6 protein were 3000-fold for LPS, threefold for 16-phe-LXA(4), eightfold for LXA(4 and) twofold for LTB4. Prior exposure of MO to 16-phe-LXA(4), but not LXA(4), reduced LTB4 induced synthesis of IL-1beta with 66%, IL-6 with 20% and IL-1Ra with 29%. Thus, a stable LXA analogue, that resists rapid inactivation by monocytes, displays novel actions in cytokine generation, intimately involved in the regulation of inflammation.