Lipoxin (LX)A4 and Aspirin-triggered 15-epi-LXA4 Inhibit Tumor Necrosis Factor 1α–initiated Neutrophil Responses and Trafficking: Regulators of a Cytokine–Chemokine Axis

Abstract

The impact of lipoxin A4 (LXA4) and aspirin-triggered lipoxins (ATLs) was investigated in tumor necrosis factor (TNF)-α–initiated neutrophil (polymorphonuclear leukocyte) responses in vitro and in vivo using metabolically stable LX analogues. At concentrations as low as 1–10 nM, the LXA4 and ATL analogues each inhibited TNF-α–stimulated superoxide anion generation and IL-1β release by human polymorphonuclear leukocytes. These LXA4-ATL actions were time and concentration dependent and proved selective for TNF-α, as these responses were not altered with either GM-CSF– or zymosan-stimulated cells. TNF-α–induced IL-1β gene expression was also regulated by both anti-LXA4 receptor antibodies and LXA4-ATL analogues. In murine air pouches, 15R/S-methyl-LXA4 dramatically inhibited TNF-α–stimulated leukocyte trafficking, as well as the appearance of both macrophage inflammatory peptide 2 and IL-1β, while concomitantly stimulating IL-4 in pouch exudates. Together, these results indicate that both LXA4 and ATL regulate TNF-α–directed neutrophil actions in vitro and in vivo and stimulate IL-4 in exudates, playing a pivotal role in immune responses.

The Arthritis Severity Quantitative Trait Loci Cia4 and Cia6 Regulate Neutrophil Migration into Inflammatory Sites and Levels of TNF-α and Nitric Oxide

“…Transgenic overexpression in mice induces spontaneous arthritis (43), and TNF antagonism has been one of the most effective strategies recently developed to treat RA (44,45). TNF-␣ is also a known chemotactic factor for neutrophils (46,47), and both activates endothelial cells and increases the expression of adhesion molecules (48, 49) further promoting leukocyte transmigration. Increased levels of TNF-␣ can be detected as early as 2h after the carrageenan injection in air pouches and precede the neutrophilic infiltration (50), supporting the concept of a key role in chemoattraction of these cells (47).…”

“…TNF-␣ is also a known chemotactic factor for neutrophils (46,47), and both activates endothelial cells and increases the expression of adhesion molecules (48, 49) further promoting leukocyte transmigration. Increased levels of TNF-␣ can be detected as early as 2h after the carrageenan injection in air pouches and precede the neutrophilic infiltration (50), supporting the concept of a key role in chemoattraction of these cells (47). Pouch lining macrophages, mast cells and fibroblasts contribute to the early levels of TNF-␣.…”

An Aspirin-Triggered Lipoxin A4 Stable Analog Displays a Unique Topical Anti-Inflammatory Profile

“…1 and references therein). In TNF-␣-induced dorsal air pouch inflammation, stable LXA 4 analogs have potent local and systemic anti-inflammatory efficacy via downregulation of proinflammatory cytokine and chemokine networks (11,12). More specifically, lipoxins inhibit cytokine-stimulated IL-1␤, macrophage inflammatory protein-2, and superoxide production while stimulating the anti-inflammatory cytokine IL-4 in neutrophils (11).…”

Lipoxin agonists: turn right! to path of resolving neutrophil

“…It is clear that resolution of an inflammatory reaction occurs at many levels of signal transduction and involves crosstalk between multiple proinflammatory and anti-inflammatory pathways. In PMNs, some key protective cellular mechanisms that exert counterregulation of pro-inflammatory signals are attributed to: inhibition of signaling from cell surface receptors (Takano et al 1997); clearance of lipid mediators (Devchand et al 1996); inhibition of pro-inflammatory transcription factor activation pathways (Delerive et al 1998); metabolic conversion of pro-inflammatory lipid mediators to anti-inflammatory mediators (Serhan 1997); and modulation of the chemokine-cytokine axis (Hachicha et al 1999). More recent efforts have identified a nuclear co-repressor as an inducible switch associated with a resolution program, consistent with the notion that a "resolving neutrophil" has its own fingerprint of expressed genes (Qui et al 2001).…”

“…ATLa can also redefine the chemokine-cytokine axis in human PMNs, to downregulate the expression of pro-inflammatory peptides and upregulate the expression of anti-inflammatory peptides (Hachicha et al 1999). For example, in human PMNs, ATLa decreases levels of TNFα-stimulated IL1β transcripts.…”