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2014 ; 193
(7
): 3683-92
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Crucial role of macrophage selenoproteins in experimental colitis
#MMPMID25187657
Kaushal N
; Kudva AK
; Patterson AD
; Chiaro C
; Kennett MJ
; Desai D
; Amin S
; Carlson BA
; Cantorna MT
; Prabhu KS
J Immunol
2014[Oct]; 193
(7
): 3683-92
PMID25187657
show ga
Inflammation is a hallmark of inflammatory bowel disease (IBD) that involves
macrophages. Given the inverse link between selenium (Se) status and IBD-induced
inflammation, our objective was to demonstrate that selenoproteins in macrophages
were essential to suppress proinflammatory mediators, in part, by the modulation
of arachidonic acid metabolism. Acute colitis was induced using 4% dextran sodium
sulfate in wild-type mice maintained on Se-deficient (<0.01 ppm Se), Se-adequate
(0.08 ppm; sodium selenite), and two supraphysiological levels in the form of
Se-supplemented (0.4 ppm; sodium selenite) and high Se (1.0 ppm; sodium selenite)
diets. Selenocysteinyl transfer RNA knockout mice (Trsp(fl/fl)LysM(Cre)) were
used to examine the role of selenoproteins in macrophages on disease progression
and severity using histopathological evaluation, expression of proinflammatory
and anti-inflammatory genes, and modulation of PG metabolites in urine and
plasma. Whereas Se-deficient and Se-adequate mice showed increased colitis and
exhibited poor survival, Se supplementation at 0.4 and 1.0 ppm increased survival
of mice and decreased colitis-associated inflammation with an upregulation of
expression of proinflammatory and anti-inflammatory genes. Metabolomic profiling
of urine suggested increased oxidation of PGE2 at supraphysiological levels of Se
that also correlated well with Se-dependent upregulation of 15-hydroxy-PG
dehydrogenase (15-PGDH) in macrophages. Pharmacological inhibition of 15-PGDH,
lack of selenoprotein expression in macrophages, and depletion of infiltrating
macrophages indicated that macrophage-specific selenoproteins and upregulation of
15-PGDH expression were key for Se-dependent anti-inflammatory and proresolving
effects. Selenoproteins in macrophages protect mice from dextran sodium
sulfate-colitis by enhancing 15-PGDH-dependent oxidation of PGE2 to alleviate
inflammation, suggesting a therapeutic role for Se in IBD.
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