Molecular mechanisms of extracellular adenine nucleotides-mediated inhibition of human Cd4(+) T lymphocytes activation.

We have previously reported that ATPgammaS, a slowly hydrolyzed analog of ATP, inhibits the activation of human CD4(+) T lymphocytes by anti-CD3 and anti-CD28 mAb. In this report we have partially characterized the signaling mechanisms involved in this immunosuppressive effect. ATPgammaS had no inhibitory effect on CD4(+) T-cell activation induced by PMA and anti-CD28, indicating that it acts proximally to the TCR.

The house dust mite allergen Der p 1, unlike Der p 3, stimulates the expression of interleukin-8 in human airway epithelial cells via a proteinase-activated receptor-2-independent mechanism.

We investigated and compared the mechanisms by which two dust mite proteolytic allergens, Der p 1 and Der p 3, and a peptide agonist of proteinase-activated receptor 2 (PAR(2)AP) trigger interleukin (IL)-8 release from human pulmonary epithelial cells (A549). Although all three stimuli tested induced the up-regulation of IL-8 (mRNA and protein), the Der p 1-mediated signaling events did not exactly match those induced by PAR(2)AP and Der p 3. First, Der p 1 was less effective in stimulating IL-8 gene transcriptional activity than PAR(2)AP and Der p 3.

Extracellular adenine nucleotides inhibit the activation of human CD4+ T lymphocytes.

ATP has been reported to inhibit or stimulate lymphoid cell proliferation, depending on the origin of the cells. Agents that increase cAMP, such as PGE(2), inhibit human CD4(+) T cell activation. We demonstrate that several ATP derivatives increase cAMP in both freshly purified and activated human peripheral blood CD4(+) T cells.

The P2Y11 receptor mediates the ATP-induced maturation of human monocyte-derived dendritic cells.

Recently, it has been shown that ATP and TNF-alpha synergize in the activation and maturation of human dendritic cells (DC); the effect of ATP was reproduced by hydrolysis-resistant derivatives of ATP and was blocked by suramin, suggesting the involvement of a P2 receptor, but the particular subtype involved was not identified. In this report we confirm that ATP and various derivatives synergize with TNF-alpha and LPS to induce the maturation of human monocyte-derived DC, as revealed by up-regulation of the CD83 marker and the secretion of IL-12. The rank order of potency of various analogs (AR-C67085 > adenosine 5'-O-(3-thiotriphosphate) = 2'- and 3'-O-(4-benzoyl-benzoyl) ATP > ATP > 2-methylthio-ATP) was close to that of the recombinant human P2Y11 receptor.

SODs are involved in the regulation of ICAM-1 expression in human melanoma and endothelial cells.

It is well known that ICAM-1 expression can be stimulated by TNF and by oxidative stress, via the activation of specific transcription factors. Two of these--NFkappaB and AP-1--can also be activated by reactive oxygen species, including the superoxide anion (also produced under TNF challenge). The latter is inactivated by superoxide dismutase of which two forms exist: Cu/Zn-SOD (cytoplasmic) and Mn-SOD (mitochondrial).