Altered endocrine and autocrine metabolism of vitamin D in a mouse model of gastrointestinal inflammation.
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.
Department of Orthopaedic Surgery, David Geffen School of Medicine, UCLA, 615 Charles E. Young Drive South, Los Angeles, California 90095, USA.
Nancy
N
Liu
Lisa
L
Nguyen
Rene F
RF
Chun
Venu
V
Lagishetty
Songyang
S
Ren
Shaoxing
S
Wu
Bruce
B
Hollis
Hector F
HF
DeLuca
John S
JS
Adams
Martin
M
Hewison
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology; D002117:Calcitriol / Q000097:blood*; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D003106:Colon / Q000201:enzymology / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004703:Endocrine System / Q000276:immunology / Q000378:metabolism*; D005759:Gastroenteritis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression / Q000276:immunology; D006706:Homeostasis / Q000502:physiology; D007668:Kidney / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D014808:Vitamin D Deficiency / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016264:Dextran Sulfate; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol