TY - JOUR
T1 - Ablation of Gly96/immediate early gene-X1 (gly96/iex-1) aggravates DSS-induced colitis in mice
T2 - Role for gly96/iex-1 in the regulation of NF-kB
AU - Sina, Christian
AU - Arlt, Alexander
AU - Gavrilova, Olga
AU - Midtling, Emilie
AU - Kruse, Marie Luise
AU - Müerköster, Susanne Sebens
AU - Kumar, Rajiv
AU - Fölsch, Ulrich R.
AU - Schreiber, Stefan
AU - Rosenstiel, Philip
AU - Schäfer, Heiner
PY - 2010
Y1 - 2010
N2 - Background: Inflammatory bowel diseases (IBDs) result from environmental and genetic factors and are characterized by an imbalanced immune response in the gut and deregulated activation of the transcription factor NF-kB. Addressing the potential role of gly96/iex-1 in the regulation of NF-kB in IBD, we used the dextran sodium sulfate (DSS) colitis model in mice in which the gly96/iex-1 gene had been deleted. Methods: C57BL/6 mice of gly96/iex-1-/- or gly96/iex-1+/+ genotype were treated continuously with 4% DSS (5 days) and repeatedly with 2% DSS (28 days) for inducing acute and chronic colitis, respectively. In addition to clinical and histological exploration, colon organ culture and bone marrow-derived cells (BMCs) were analyzed for chemo/cytokine expression and NF-kB activation. Results: Compared to wildtype littermates, gly96/iex-1-/- mice exhibited an aggravated phenotype of both acute and chronic colitis, along with a greater loss of body weight and colon length. Colonic endoscopy revealed a higher degree of hyperemia, edema, and bleeding in gly96/iex-1-/- mice, and immunohistochemistry detected massive mucosal infiltration of leukocytes and marked histological changes. The expression of proinflammatory chemoand cytokines was higher in the colon of DSS-treated gly96/iex-1-/- mice, and the NF-jB activation was enhanced particularly in the distal colon. In cultured BMCs from gly96/iex-1-/- mice, Pam3Cys4 treatment induced expression of proinflammatory mediators to a higher degree than in gly96/iex-1+/+ BMCs, along with greater NF-kB activation. Conclusions: Based on the observation that genetic ablation of gly96/iex-1 triggers intestinal inflammation in mice, we demonstrate for the first time that gly96/iex-1 exerts strong antiinflammatory activity via its NF-kB-counterregulatory effect.
AB - Background: Inflammatory bowel diseases (IBDs) result from environmental and genetic factors and are characterized by an imbalanced immune response in the gut and deregulated activation of the transcription factor NF-kB. Addressing the potential role of gly96/iex-1 in the regulation of NF-kB in IBD, we used the dextran sodium sulfate (DSS) colitis model in mice in which the gly96/iex-1 gene had been deleted. Methods: C57BL/6 mice of gly96/iex-1-/- or gly96/iex-1+/+ genotype were treated continuously with 4% DSS (5 days) and repeatedly with 2% DSS (28 days) for inducing acute and chronic colitis, respectively. In addition to clinical and histological exploration, colon organ culture and bone marrow-derived cells (BMCs) were analyzed for chemo/cytokine expression and NF-kB activation. Results: Compared to wildtype littermates, gly96/iex-1-/- mice exhibited an aggravated phenotype of both acute and chronic colitis, along with a greater loss of body weight and colon length. Colonic endoscopy revealed a higher degree of hyperemia, edema, and bleeding in gly96/iex-1-/- mice, and immunohistochemistry detected massive mucosal infiltration of leukocytes and marked histological changes. The expression of proinflammatory chemoand cytokines was higher in the colon of DSS-treated gly96/iex-1-/- mice, and the NF-jB activation was enhanced particularly in the distal colon. In cultured BMCs from gly96/iex-1-/- mice, Pam3Cys4 treatment induced expression of proinflammatory mediators to a higher degree than in gly96/iex-1+/+ BMCs, along with greater NF-kB activation. Conclusions: Based on the observation that genetic ablation of gly96/iex-1 triggers intestinal inflammation in mice, we demonstrate for the first time that gly96/iex-1 exerts strong antiinflammatory activity via its NF-kB-counterregulatory effect.
KW - Cytokines
KW - Feedback regulation
KW - Intestinal inflammation
KW - Signal transduction
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U2 - 10.1002/ibd.21066
DO - 10.1002/ibd.21066
M3 - Article
C2 - 19714745
AN - SCOPUS:73949136139
SN - 1078-0998
VL - 16
SP - 320
EP - 331
JO - Inflammatory bowel diseases
JF - Inflammatory bowel diseases
IS - 2
ER -