Aspirin-triggered lipoxin A4 and B4 analogs block extracellular signal-regulated kinase-dependent TNF-alpha 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 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-alpha from human PBMC after stimulation by anti-CD3 Abs, with the IC(50) value of approximately 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-alpha 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-alpha 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.
Ariel
Amiram
A
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, USA.
Chiang
Nan
N
Arita
Makoto
M
Petasis
Nicos A
NA
Serhan
Charles N
CN
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D002469:Cell Separation; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D007106:Immune Sera / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D044045:Lipoxins; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002070:Butadienes; D017252:CD3 Complex; C105101:FPR2 protein, human; D006893:Hydroxyeicosatetraenoic Acids; D007106:Immune Sera; D007166:Immunosuppressive Agents; D044045:Lipoxins; D009570:Nitriles; D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; C040527:lipoxin A4; C042651:lipoxin B4; D020928:Mitogen-Activated Protein Kinases; D001241:Aspirin