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

A Ariel, N Chiang, M Arita, NA Petasis… - The Journal of …, 2003 - journals.aai.org
The Journal of Immunology, 2003journals.aai.org
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 LXA 4-stable analogs (ATLa) on human T cell functions. 15-epi-16-
(p-fluoro) phenoxy-LXA 4 (ATLa 1) blocked the secretion of TNF-α from human PBMC after
stimulation by anti-CD3 Abs, with the IC 50 value of≈ 0.05 nM. A similar action was also
exerted by the native aspirin-triggered 15-epi-LXA 4, a new 15-epi-16-(p-trifluoro) phenoxy …
Abstract
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 LXA 4-stable analogs (ATLa) on human T cell functions. 15-epi-16-(p-fluoro) phenoxy-LXA 4 (ATLa 1) blocked the secretion of TNF-α from human PBMC after stimulation by anti-CD3 Abs, with the IC 50 value of≈ 0.05 nM. A similar action was also exerted by the native aspirin-triggered 15-epi-LXA 4, a new 15-epi-16-(p-trifluoro) phenoxy-LXA 4 analog (ATLa 2), as well as LXB 4, and its analog 5-(R/S)-methyl-LXB 4. The LXA 4 receptor (ALX) is expressed in peripheral blood T cells and mediates the inhibition of TNF-α secretion from activated T cells by ATLa 1. 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 aspirin-triggered 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.
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