Premium
Accumulation of nuclear [beta]‐catenin in dendritic cells from NOD mice is responsible for the pro‐inflammatory phenotype of these cells
Author(s) -
Villard Marine,
Martin Michael,
Carabeo Rey A,
Manirarora Jean N,
Parnell Sarah A,
Kosiewicz Michele M,
Alard Pascale
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1074.31
Subject(s) - nod , downregulation and upregulation , proinflammatory cytokine , gsk 3 , nod mice , cytokine , gsk3b , catenin , microbiology and biotechnology , inflammation , chemistry , phosphorylation , cancer research , immunology , biology , signal transduction , endocrinology , wnt signaling pathway , diabetes mellitus , biochemistry , gene
Pro‐inflammatory cytokines appear to mediate Type I diabetes development, and suppression of pro‐inflammatory cytokines in NOD mice is associated with prevention of diabetes onset. Antigen presenting cells in NOD mice produce higher levels of the pro‐inflammatory cytokine, IL‐12, due to NFκB hyperactivity. GSK3 is a crucial modulator of pro‐versus anti‐inflammatory cytokines, since its inhibition following phosphorylation by Akt leads to the impairment in IL‐12 production and to the increase in anti‐inflammatory cytokine, IL‐10, by DC. We, therefore, examined whether the pro‐inflammatory phenotype of NOD DC was due to the alteration of GSK3 activity. We have found that the levels of GSK3 phosphorylation were identical in NOD DC versus B6 DC. However, the levels of phosphorylated β‐catenin and glycogen synthase, two GSK3 targets, were elevated. Interestingly, there was a dramatic accumulation of β‐catenin in the nucleus of NOD DC compared to B6 DC. Knocking‐down β‐catenin with β‐catenin siRNA led to the downregulation of IL‐12 and upregulation of IL‐10 production by NOD DC. Altogether, these data indicate that NOD DC exhibit a defect in the expression of β‐catenin, which upon accumulation in the nucleus appears to be responsible for the pro‐inflammatory phenotype of these cells. (‐catenin has, therefore, the potential to be a new therapeutic target for the prevention and/or treatment of type 1 diabetes.