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

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 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 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.

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

“…p38-MAPK provides a proapoptotic/"death" signal for neutrophils that can be overridden by a survival signal generated by p42/p44-ERK (49). Treatment of human T cells with 10 nM ATLa for 6 h blocks activation of ERK and release of TNF-␣ upon subsequent stimulation of these cells with an anti-CD3 Ab (50). These data are consistent with ATLa blocking the proinflammatory effects of a variety of immune cells by targeting MAPKs.…”

The Required Role of Endogenously Produced Lipoxin A4 and Annexin-1 for the Production of IL-10 and Inflammatory Hyporesponsiveness in Mice

“…ANXA-1 has been shown to promote the detachment of neutrophils adhered to the inflamed endothelium, hence reducing the number of cells that migrate into the subendothelial space (51). In addition, the latter mediators have also been shown to prevent the production of TNF-␣ in various models of inflammation (52,53). As neutrophils and TNF-␣ cooperate to mediate reperfusion-induced injury and lethality, the above-mentioned effects could account for the protective effects of LXA 4 and ANXA-1 in mice.…”

The Docosatriene Protectin D1 Is Produced by TH2 Skewing and Promotes Human T Cell Apoptosis via Lipid Raft Clustering

“…T Cell Incubations-Cytokines (TNF␣ and IFN␥) produced by human T cells were determined as described in Ariel et al (28). Briefly, human peripheral blood T cells were incubated with increasing concentrations of PD1 or vehicle (0.05% EtOH) for 6 h at 37°C and then in 48-well plates coated with anti-CD3 ϩ anti-CD28 (2 g/ml each) or anti-CD3 alone and cultured for 41 h. The supernatants were collected from the wells and evaluated for TNF␣ and IFN␥ content by a standard enzyme-linked immunosorbent assay.…”

“…2) suggested that lymphocytes are one of the main targets of PD1. Next we examined the impact of PD1 on the secretion of cytokines by human peripheral blood T cells because cytokine deprivation per se participates in the resolution of inflammation and is regulated by other lipid mediators of resolution, such as lipoxins (28). Antibodies against CD3 and CD28 were used to mimic the stimulation by antigen-presenting cells that leads to the secretion of TNF␣ and IFN␥ by T cells.…”