The active form of
vitamin D,
1,25-dihydroxyvitamin D3, [
1,25(OH)2D3] has potent actions on innate and adaptive immunity. Although endocrine synthesis of
1,25(OH)2D3 takes place in the kidney, the
enzyme that catalyzes this, 25-hydroxyvitamin D-1alpha-hydroxylase (
CYP27b1 in humans,
Cyp27b1 in mice), is expressed at many extra-renal sites including the colon. We have shown previously that colonic expression of
CYP27b1 may act to protect against the onset of
colitis. To investigate this further, we firstly characterized changes in
Cyp27b1 expression in a mouse model of
colitis. Mice treated with
dextran sodium sulfate (DSS) showed
weight loss, histological evidence of
colitis, and increased expression of inflammatory
cytokines. This was associated with decreased renal expression of
Cyp27b1 (5-fold, P=0.013) and lower serum
1,25(OH)2D3 (51.8+/-5.9 pg/nl vs. 65.1+/-1.6 in controls, P<0.001). However, expression of
CYP27b1 was increased in the proximal colon of DSS mice (4-fold compared with controls, P<0.001). Further studies were carried out using
Cyp27b1 null (-/-) mice. Compared with+/-controls the
Cyp27b1-/-mice showed increased
weight loss (4.9% vs. 22.8%, P<0.001) and
colitis. This was associated with raised
IL-1 in the distal colon and
IL-17 in the proximal and distal colon. Conversely, DSS-treated
Cyp27b1-/-mice exhibited lower
IL-10 in the proximal colon and
toll-like receptors 2 and 4 in the distal colon. These data indicate that both local and endocrine synthesis of
1,25(OH)2D3 affect
colitis in DSS-treated mice. Lack of
Cyp27b1 exacerbates disease in this model, suggesting that similar effects may occur with
vitamin D deficiency.