Abstract
Vanin-1 is a membrane-anchored pantetheinase highly expressed in the gut and liver. It hydrolyzes pantetheine to pantothenic acid (vitamin B5) and the low-molecular-weight thiol cysteamine. The latter is believed to be a key regulating factor of several essential metabolic pathways, acting through sulfhydryl-disulfide exchange reactions between sulfhydryl groups of the enzymes and the oxidized form, cystamine. Its physiological importance remains to be elucidated, however. To explore this point, we developed Vanin-1-deficient mice that lack free cysteamine. We examined the susceptibility of deficient mice to intestinal inflammation, either acute (NSAID administration) or chronic (Schistosoma infection). We found that Vanin-1(-/-) mice better controlled inflammatory reaction and intestinal injury in both experiments. This protection was associated with increased gamma-glutamylcysteine synthetase activity and increased stores of reduced glutathione, as well as reduced inflammatory cell activation in inflamed tissues. Oral administration of cystamine reversed all aspects of the deficient phenotype. These findings suggest that one cysteamine function is to upregulate inflammation. Consequently, the pantetheinase activity of Vanin-1 molecule could be a target for a new anti-inflammatory strategy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amidohydrolases
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / toxicity*
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism*
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Chemokine CXCL2
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Chemokines / genetics
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Chemokines / metabolism
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Cyclooxygenase 1
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Cyclooxygenase 2
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Cysteamine / metabolism
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GPI-Linked Proteins
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Glutamate-Cysteine Ligase / metabolism
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Glutathione / metabolism*
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Indomethacin / toxicity*
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Inflammation / chemically induced
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Inflammation / metabolism
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Inflammation / pathology*
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Intestinal Mucosa / metabolism
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Intestines / cytology
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Intestines / parasitology
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Intestines / pathology*
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Membrane Proteins
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / metabolism
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Schistosoma mansoni / metabolism*
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Schistosomiasis mansoni / metabolism
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Schistosomiasis mansoni / pathology*
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Survival Rate
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Cell Adhesion Molecules
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Chemokine CXCL2
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Chemokines
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Cxcl2 protein, mouse
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GPI-Linked Proteins
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Isoenzymes
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Membrane Proteins
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Cysteamine
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Cyclooxygenase 1
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Cyclooxygenase 2
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Prostaglandin-Endoperoxide Synthases
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Ptgs1 protein, mouse
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Amidohydrolases
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pantetheinase
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Glutamate-Cysteine Ligase
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Glutathione
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Indomethacin