Interactions Between Lipoxin A₄, the Stable Analogue 16‐phenoxy‐lipoxin A₄ and Leukotriene B₄ in Cytokine Generation by Human Monocytes

Abstract

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 19, ) modulated the ability of human blood monocytes (MO) to express mRNA and proteins for interleukin-1b (IL-1b), IL-6 and IL-1 receptor antagonist (IL-1Ra) in vitro and compared their actions with lipopolysaccharide (LPS) and leukotriene B 4 (LTB 4 ). 16-phe-LXA 4 , LPS and LTB 4 , but not LXA 4 , induced gene expression of IL-1b in MO. IL-1b protein synthesis increased by LPS (1500-fold), LTB 4 (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 LTB 4 (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 LXA4 and twofold for LTB 4 . Prior exposure of MO to 16-phe-LXA 4 , but not LXA 4 , reduced LTB 4 induced synthesis of IL-1b 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.

ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance

“…5,6 Potential local effects of leukotrienes in adipose tissue include macrophage recruitment, nitric oxide synthesase (NOS) production, induction of MCP-1, 11 and IL6 production. 28 These effectors are implicated both in inducing local insulin resistance in the adipose tissue and could also, by secretion into the circulation or changing the secretory function of adipocytes, contribution to generalized insulin resistance and, ultimately, the development of CVD.…”

Novel Lipid Mediators and Resolution Mechanisms in Acute Inflammation

“…25,35 Notably, a stable lipoxin analog, 16-phenoxy-LXA 4 , stimulates mononuclear cells to produce IL-1Ra, the endogenous receptor antagonist. 94 …”

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

“…Contrary to the majority of LOX products, LXA 4 and LXB 4 have shown to generate effective anti-inflammatory responses, which may antagonize pro-inflammatory signals mediated by other LOX catalyzed AA derivatives [84].…”