Id1 expression in endothelial cells of the colon is required for normal response to injury.
Inhibitor of DNA binding (ID)-1 is important for angiogenesis during embryogenesis and tumor development. Whether ID1 expression in endothelial cells of the colon is required for normal response to injury is unknown. We demonstrate that Id1 is up-regulated in colonic endothelial cells in an experimental model of colitis and in the inflamed mucosa of patients with inflammatory bowel disease. Because prostaglandin E2 and tumor necrosis factor-α are also elevated in colitis, we determined whether these factors could induce ID1 transcription in cultured endothelial cells. Tumor necrosis factor-α stimulated ID1 transcription via early growth response 1 protein (Egr-1). By contrast, the induction of ID1 by prostaglandin E2 was mediated by cAMP response element-binding protein (CREB). To determine whether the increased ID1 levels in the endothelial cells of inflamed mucosa were an adaptive response that modulated the severity of tissue injury, Id1 was conditionally depleted in the endothelium of mice, which sensitized the mice to more severe chemical colitis, including more severe diarrhea, bleeding, and histological injury, and shorter colon compared with control mice. Moreover, depletion of Id1 in the vasculature was associated with increased CD31(+) aggregates and increased vascular permeability in inflamed mucosa compared with those in Id1 wild-type control mice. These results suggest that endothelial ID1 up-regulation in inflamed colonic mucosa is an adaptive response that modulates the severity of tissue injury.
Department of Medicine, Weill Cornell Medical College, New York, New York; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Ning
N
Zhang
Department of Medicine, Weill Cornell Medical College, New York, New York.
Kotha
K
Subbaramaiah
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
Rhonda K
RK
Yantiss
Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, New York.
Xi Kathy
XK
Zhou
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Yvette
Y
Chin
Department of Medicine, Weill Cornell Medical College, New York, New York.
Ellen J
EJ
Scherl
Department of Medicine, Weill Cornell Medical College, New York, New York.
Brian P
BP
Bosworth
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address: benezrar@mskcc.org.
Robert
R
Benezra
Department of Medicine, Weill Cornell Medical College, New York, New York. Electronic address: ajdannen@med.cornell.edu.
Andrew J
AJ
Dannenberg
D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004727:Endothelium / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism* / Q000473:pathology; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D014409:Tumor Necrosis Factor-alpha