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.
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Authors | Vincenzo Brancaleone, Emma Mitidieri, Roderick J Flower, Giuseppe Cirino, Mauro Perretti |
Journal | The Journal of pharmacology and experimental therapeutics
(J Pharmacol Exp Ther)
Vol. 351
Issue 1
Pg. 96-104
(Oct 2014)
ISSN: 1521-0103 [Electronic] United States |
PMID | 25077524
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics. |
Chemical References |
- Annexin A1
- Interleukin-1beta
- Lipopolysaccharides
- RNA, Messenger
- Sulfides
- annexin A1, mouse
- Nitric Oxide Synthase Type II
- Cyclooxygenase 2
- Cystathionine beta-Synthase
- Cystathionine gamma-Lyase
- sodium bisulfide
- Hydrogen Sulfide
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Topics |
- Animals
- Annexin A1
(genetics, metabolism)
- Aorta
(metabolism)
- Bone Marrow Cells
(drug effects, metabolism)
- Cell Adhesion
- Cell Movement
- Cyclooxygenase 2
(genetics, metabolism)
- Cystathionine beta-Synthase
(genetics, metabolism)
- Cystathionine gamma-Lyase
(genetics, metabolism)
- Female
- Humans
- Hydrogen Sulfide
(metabolism)
- Inflammation
(metabolism)
- Interleukin-1beta
(pharmacology)
- Kidney
(metabolism)
- Leukocytes
(metabolism, physiology)
- Lipopolysaccharides
(pharmacology)
- Macrophages
(drug effects, metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Neutrophils
(drug effects, metabolism)
- Nitric Oxide Synthase Type II
(genetics, metabolism)
- RNA, Messenger
(genetics, metabolism)
- Spleen
(metabolism)
- Sulfides
(pharmacology)
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