New Insights into the Pro-Inflammatory Activities of Ang1 on Neutrophils: Induction of MIP-1? Synthesis and Release.
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ABSTRACT: We reported the expression of angiopoietin Tie2 receptor on human neutrophils and the capacity of angiopoietins (Ang1 and Ang2) to induce pro-inflammatory activities, such as platelet-activating factor synthesis, ?2-integrin activation and neutrophil migration. Recently, we observed differential effects between both angiopoietins, namely, the capacity of Ang1, but not Ang2, to promote rapid interleukin-8 synthesis and release, as well as neutrophil viability. Herein, we addressed whether Ang1 and/or Ang2 could modulate the synthesis and release of macrophage inflammatory protein-1? (MIP-1?) by neutrophils. Neutrophils were isolated from blood of healthy volunteers; intracellular and extracellular MIP-1? protein concentrations were assessed by ELISA. After 24 hours, the basal intracellular and extracellular MIP-1? protein concentrations were ?500 and 100 pg/106 neutrophils, respectively. Treatment with Ang1 (10 nM) increased neutrophil intracellular and extracellular MIP-1? concentrations by 310 and 388% respectively. Pretreatment with PI3K (LY294002), p38 MAPK (SB203580) and MEK (U0126) inhibitors completely inhibited Ang1-mediated increase of MIP-1? intracellular and extracellular protein levels. Pretreatment with NF-?B complex inhibitors, namely Bay11-7085 and IKK inhibitor VII or with a transcription inhibitor (actinomycin D) and protein synthesis inhibitor (cycloheximide), did also abrogate Ang1-mediated increase of MIP-1? intracellular and extracellular protein levels. We validated by RT-qPCR analyses the effect of Ang1 on the induction of MIP-1? mRNA levels. Our study is the first one to report Ang1 capacity to induce MIP-1? gene expression, protein synthesis and release from neutrophils, and that these effects are mediated by PI3K, p38 MAPK and MEK activation and downstream NF-?B activation.
SUBMITTER: Dumas E
PROVIDER: S-EPMC5025150 | biostudies-literature | 2016
REPOSITORIES: biostudies-literature
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