title: Angiopoietin-1 upregulates de novo expression of IL-1β and Il1-Ra, and the exclusive release of Il1-Ra from human neutrophils.
abstract: The expression of the angiopoietin (Ang) receptor, Tie2, on both endothelial and inflammatory cells supports the idea that Ang signaling may play a fundamental role in initiating and maintaining the inflammatory response. We have previously shown that Ang1 and/or Ang2 alter the innate immune response by enhancing human neutrophil survival, chemotaxis and production of inflammatory cytokine interleukin-8 (IL-8) in vitro. Thus, we hypothesized that Ang1 and Ang2 could modulate other inflammatory signals in neutrophils, a possibility we explored through a gene-based assay looking at changes in the mRNA expression of 84 inflammatory cytokines and their receptors. We observed that Ang1 (10(-8) M), but not Ang2, increased mRNA expression of prominent pro-inflammatory cytokine IL-1β and its natural antagonist IL-1RA, by up to 32.6- and 10.0-fold respectively, compared to PBS-control. The effects of Ang1 extended to the proteins, as Ang1 increased intracellular levels of precursor and mature IL-1β, and extracellular levels of IL-1RA proteins, by up to 4.2-, 5.0- and 4.4-fold respectively, compared to PBS-control. Interestingly, Ang1 failed at inducing IL-1β protein release or at increasing intracellular IL-1RA, but the ratio of IL-1RA to mature IL-1β remained above 100-fold molar excess inside and outside the cells. The above-noted effects of Ang1 were mediated by MAP kinases, whereby inhibiting MEK1/2 lead to up to 70% effect reduction, whereas the blockade of p38MAPK activity doubled Ang1's effect. These findings suggest that Ang1 selectively alters the balance of neutrophil-derived inflammatory cytokines, favoring the blockade of IL-1 activity, a consideration for future therapies of inflammatory diseases.
authors.affiliation: Research Center, Montreal Heart Institute, Montréal, Canada ; Department Of Pharmacology, Faculty of Medicine, Université De Montréal, Montréal, Canada.
authors.forename: Lydia E
authors.initials: LE
authors.lastname: Haddad
authors.affiliation: Research Center, Montreal Heart Institute, Montréal, Canada ; Department Of Pharmacology, Faculty of Medicine, Université De Montréal, Montréal, Canada.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Sirois
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism*; D002633:Chemotaxis; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D020935:MAP Kinase Signaling System; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; D011188:Potassium