title: Annexin A1 mediates hydrogen sulfide properties in the control of inflammation.
abstract: Hydrogen sulfide (H2S) is a gaseous mediator synthesized in mammalian tissues by three main enzymes-cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate-sulfurtransferase-and its levels increase under inflammatory conditions or sepsis. Since H2S and H2S-releasing molecules afford inhibitory properties in leukocyte trafficking, we tested whether endogenous annexin A1 (AnxA1), a glucocorticoid-regulated inhibitor of inflammation acting through formylated-peptide receptor 2 (ALX), could display intermediary functions in the anti-inflammatory profile of H2S. We first investigated whether endogenous AnxA1 could modulate H2S biosynthesis. To this end, a marked increase in CBS and/or CSE gene products was quantified by quantitative real-time polymerase chain reaction in aortas, kidneys, and spleens collected from AnxA1(-/-) mice, as compared with wild-type animals. When lipopolysaccharide-stimulated bone marrow-derived macrophages were studied, H2S-donor sodium hydrosulfide (NaHS) counteracted the increased expression of inducible nitric oxide synthase and cyclooxygenase 2 mRNA evoked by the endotoxin, yet it was inactive in macrophages harvested from AnxA1(-/-) mice. Next we studied the effect of in vivo administration of NaHS in a model of interleukin-1β (IL-1β)-induced mesenteric inflammation. AnxA1(+/+) mice treated with NaHS (100 μmol/kg) displayed inhibition of IL-1β-induced leukocyte adhesion/emigration in the inflamed microcirculation, not observed in AnxA1(-/-) animals. These results were translated by testing human neutrophils, where NaHS (10-100 μM) prompted an intense mobilization (>50%) of AnxA1 from cytosol to cell surface, an event associated with inhibition of cell/endothelium interaction under flow. Taken together, these data strongly indicate the existence of a positive interlink between AnxA1 and H2S pathway, with nonredundant functions in the control of experimental inflammation.
authors: Department of Science, University of Basilicata, Potenza, Italy (V.B.); Department of Pharmacy, University of Naples, Naples, Italy (E.M., G.C.); and William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK (V.B., R.J.F., M.P.) vincenzo.brancaleone@unibas.it.
authors: Vincenzo
authors: V
authors: Brancaleone
authors: Department of Science, University of Basilicata, Potenza, Italy (V.B.); Department of Pharmacy, University of Naples, Naples, Italy (E.M., G.C.); and William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK (V.B., R.J.F., M.P.).
authors: Emma
authors: E
authors: Mitidieri
authors: Department of Science, University of Basilicata, Potenza, Italy (V.B.); Department of Pharmacy, University of Naples, Naples, Italy (E.M., G.C.); and William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK (V.B., R.J.F., M.P.).
authors: Roderick J
authors: RJ
authors: Flower
authors: Department of Science, University of Basilicata, Potenza, Italy (V.B.); Department of Pharmacy, University of Naples, Naples, Italy (E.M., G.C.); and William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK (V.B., R.J.F., M.P.).
authors: Giuseppe
authors: G
authors: Cirino
authors: Department of Science, University of Basilicata, Potenza, Italy (V.B.); Department of Pharmacy, University of Naples, Naples, Italy (E.M., G.C.); and William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK (V.B., R.J.F., M.P.).
authors: Mauro
authors: M
authors: Perretti
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism*; D001011:Aorta / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology
chemical_list: D017305:Annexin A1; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013440:Sulfides; C573274:annexin A1, mouse; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; C025451:sodium bisulfide; D006862:Hydrogen Sulfide