Aspirin-triggered lipoxin A₄ and B₄ analogs block extracellular signal-regulated kinase-dependent TNF-α secretion from human T cells

Lipoxins (LX) and their aspirin-triggered 15-epimer endogenous isoforms are endogenous anti-inflammatory and pro-resolution eicosanoids. In this study, we examined the impact of LX and aspirin-triggered LXA₄-stable analogs (ATLa) on human T cell functions. 15-epi-16-(p-fluoro)phenoxy-LXA₄ (ATLa₁) blocked the secretion of TNF-α from human PBMC after stimulation by anti-CD3 Abs, with the IC₅₀ value of ≈0.05 nM. A similar action was also exerted by the native aspirin-triggered 15-epi-LXA₄, a new 15-epi-16-(p-trifluoro)phenoxy-LXA₄ analog (ATLa₂), as well as LXB₄, and its analog 5-(R/S)-methyl-LXB₄. The LXA₄ receptor (ALX) is expressed in peripheral blood T cells and mediates the inhibition of TNF-α secretion from activated T cells by ATLa₁. This action was accomplished by inhibition of the anti-CD3-induced activation of extracellular signal-regulated kinase, which is essential for TNF-α secretion from anti-CD3-activated T cells. These results demonstrate novel roles for LX and aspirintriggered LX in the regulation of T cell-mediated responses relevant in inflammation and its resolution. Moreover, they provide potential counterregulatory signals in communication(s) between the innate and acquired immune systems.