Showing papers by "Martin Pelletier published in 2007"

Angiopoietin chemotactic activities on neutrophils are regulated by PI‐3K activation

Abstract: Angiopoietins (Ang1 and Ang2) modulate blood vessel integrity during the angiogenic process through the activation of tyrosine kinase receptor (Tie2). We recently detected Tie2 expression on neutrophils and reported that angiopoietins induce acute proinflammatory events including neutrophil beta2-integrin activation and their adhesion onto endothelial cells. Herein, we investigated the effect of angiopoietins on neutrophil migration and their capacity to modulate CXCL8/IL-8 chemotactic properties. Using a Boyden chamber assay, we observed that Ang1 and Ang2 (up to 10 nM; 60 min) increased the migration of neutrophils, and the maximal effect was achieved at 1 nM (72% and 114% increase, respectively) as compared with untreated cells. Angiopoietins induce a rapid and transient Akt phosphorylation, and pretreatment of neutrophils with PI-3K inhibitors, wortmannin (100 nM) and LY294002 (500 nM), reduced Ang1-mediated neutrophil migration by 100% and 78% and Ang2 chemotactic activity by 100% and 71%, respectively. Treatment of neutrophils with CXCL8/IL-8 (up to 50 nM; 60 min) increased basal neutrophil migration by 257% at its optimal concentration (10 nM), and pretreatment of neutrophils with corresponding PI-3K inhibitors reduced CXCL8/IL-8 (1 nM) chemotactic effect. Pretreatment of neutrophils with Ang1 or Ang2 (10 nM; 15 min) potentiated neutrophil migration induced by CXCL8/IL-8 (1 or 10 nM; 60 min) by 263% and 238% and by 177% and 164%, respectively. Finally, both angiopoietins showed a synergistic effect on the induction of Akt phosphorylation mediated by CXCL8/IL-8. In summary, our data demonstrate that angiopoietins increase neutrophil migration through PI-3K activation and can enhance proinflammatory activities of other cytokines.

Molecular mechanisms involved in interleukin-4-induced human neutrophils : expression and regulation of suppressor of cytokine signaling

Abstract: Interleukin-4 (IL-4) is a CD132-dependent cytokine known to activate the Jak-STAT pathway in different cells and cell lines. Although IL-4 has been demonstrated previously to be an agonist in human neutrophils, its capacity to activate different cell signaling pathways in these cells has never been investigated. Two types of IL-4 receptor (IL-4R) exist: the Type I (CD132/IL-4Ralpha heterodimer) and the Type II (IL-4Ralpha/IL-13Ralpha1 heterodimer). In a previous study, we demonstrated that neutrophils express the Type I receptor. Herein, using flow cytometry, we demonstrated that neutrophils, unlike U-937 cells, do not express IL-13Ralpha1 and IL-13Ralpha2 and confirmed the expression of CD132 and IL-4Ralpha on their surface. We also demonstrated that IL-4 induced phosphorylation of Syk, p38, Erk-1/2, JNK, Jak-1, Jak-2, STAT6, and STAT1 and that treatment of cells with the inhibitors piceatannol, SB203580, PD98059, or AG490 reversed the ability of IL-4 to delay neutrophil apoptosis. Using RT-PCR, we demonstrated for the first time that neutrophils express mRNA for all suppressor of cytokine signaling (SOCS) members, namely SOCS1-7 and cytokine-inducible Src homology 2 protein. It is interesting that IL-4 increased expression of SOCS3 at the mRNA and protein levels. The effect of IL-4 on SOCS3 protein expression was increased markedly when the proteasome inhibitor MG132 was added to the cultures, but this was inhibited by cycloheximide, suggesting that SOCS3 is de novo-synthesized in response to IL-4. We conclude that neutrophils express only the Type I IL-4R on their surface and that IL-4 signals via different cell signaling pathways, including the Jak/STAT/SOCS pathway.

Biological functions of interleukin-21 and its role in inflammation.

Abstract: Interleukin-21 (IL-21), the most recently discovered CD132-dependent cytokine, is mainly produced by activated T lymphocytes, particularly the inflammatory Th17 subset, and is believed to be a key factor in the transition between innate and acquired immunity. In the last few years, this cytokine has been shown to modulate the functions of T, B, and NK cells, as well as cells of myeloid origin. In addition, it was demonstrated that IL-21 is a potent antitumor agent, making it a promising candidate for the development of therapeutic tools. IL-21 has also been associated with different autoimmune and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. This review will summarize the biological functions of IL-21 and its potential role in inflammation.