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-kappaB. Addressing the potential role of gly96/iex-1 in the regulation of NF-kappaB 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-kappaB 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 chemo- and cytokines was higher in the colon of DSS-treated gly96/iex-1(-/-) mice, and the NF-kappaB activation was enhanced particularly in the distal colon. In cultured BMCs from gly96/iex-1(-/-) mice, Pam(3)Cys(4) treatment induced expression of proinflammatory mediators to a higher degree than in gly96/iex-1(+/+) BMCs, along with greater NF-kappaB 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-kappaB-counterregulatory effect.
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-kappaB. Addressing the potential role of gly96/iex-1 in the regulation of NF-kappaB 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-kappaB 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 chemo- and cytokines was higher in the colon of DSS-treated gly96/iex-1(-/-) mice, and the NF-kappaB activation was enhanced particularly in the distal colon. In cultured BMCs from gly96/iex-1(-/-) mice, Pam(3)Cys(4) treatment induced expression of proinflammatory mediators to a higher degree than in gly96/iex-1(+/+) BMCs, along with greater NF-kappaB 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-kappaB-counterregulatory effect.
Authors: Stacy L Sommer; Theresa J Berndt; Elena Frank; Jeetendra B Patel; Margaret M Redfield; Xiangyang Dong; Matthew D Griffin; Joseph P Grande; Jan M A van Deursen; Gary C Sieck; Juan C Romero; Rajiv Kumar Journal: J Appl Physiol (1985) Date: 2005-09-15
Authors: Osamu Hitotsumatsu; Regina-Celeste Ahmad; Rita Tavares; Min Wang; Dana Philpott; Emre E Turer; Bettina L Lee; Nataliya Shiffin; Rommel Advincula; Barbara A Malynn; Catherine Werts; Averil Ma Journal: Immunity Date: 2008-03 Impact factor: 31.745
Authors: Christine M Costello; Nancy Mah; Robert Häsler; Philip Rosenstiel; Georg H Waetzig; Andreas Hahn; Tim Lu; Yesim Gurbuz; Susanna Nikolaus; Mario Albrecht; Jochen Hampe; Ralph Lucius; Günther Klöppel; Holger Eickhoff; Hans Lehrach; Thomas Lengauer; Stefan Schreiber Journal: PLoS Med Date: 2005-08-23 Impact factor: 11.069
Authors: Shelly R Calcagno; Shuhua Li; Muhammad W Shahid; Michael B Wallace; Michael Leitges; Alan P Fields; Nicole R Murray Journal: Inflamm Bowel Dis Date: 2010-11-15 Impact factor: 5.325
Authors: Kimberly R Jordan; Matthew J Sikora; Jill E Slansky; Angela Minic; Jennifer K Richer; Marisa R Moroney; Junxiao Hu; Rebecca J Wolsky; Zachary L Watson; Tomomi M Yamamoto; James C Costello; Aaron Clauset; Kian Behbakht; T Rajendra Kumar; Benjamin G Bitler Journal: Clin Cancer Res Date: 2020-09-14 Impact factor: 12.531
Authors: Florian Bär; Bandik Föh; René Pagel; Torsten Schröder; Heidi Schlichting; Misa Hirose; Susanne Lemcke; Antje Klinger; Peter König; Christian M Karsten; Jürgen Büning; Hendrik Lehnert; Klaus Fellermann; Saleh M Ibrahim; Christian Sina Journal: PLoS One Date: 2014-07-22 Impact factor: 3.240