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Aspirin-Triggered Lipoxin A₄ and B₄ Analogs Block Extracellular Signal-Regulated Kinase-Dependent TNF- Secretion from Human T Cells ¹

Amiram Ariel^*, Nan Chiang^*, Makoto Arita^*, Nicos A. Petasis and Charles N. Serhan^2,*

^* Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115; and Department of Chemistry, University of Southern California, Los Angeles, CA 90089

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- 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- 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- 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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