AIM:Eph receptor tyrosine kinases and their membrane bound receptor-like ligands, the ephrins, represent a bi-directional cell-cell contact signaling system that directs epithelial movements in development. The meanin...AIM:Eph receptor tyrosine kinases and their membrane bound receptor-like ligands, the ephrins, represent a bi-directional cell-cell contact signaling system that directs epithelial movements in development. The meaning of this system in the adult human gut is unknown. We investigated the Eph/ephrin mRNA expression in the intestinal epithelium of healthy controls and patients with inflammatory bowel disease (IBD). METHODS: mRNA expression profiles of all Eph/ephrin family members in normal small intestine and colon were established by real-time RT-PCR. In addition, differential expression in IBD was investigated by cDNA array technology, and validated by both real-time RT-PCR and immunohistochemistry. Potential effects of enhanced EphB/ephrin-B signaling were analyzed in an in vitro IEC-6 cell scratch wound model. RESULTS: Human adult intestinal mucosa exhibits a complex pattern of Eph receptors and ephrins. Beside the known prominent co-expression of EphA2 and ephrinAl, we found abundantly co-expressed EphB2 and ephrin-B1/2. Interestingly, cDNA array data, validated by real-time PCR and immunohistochemistry, showed upregulation of ephrin-B2 in both perilesional and lesional intestinal epithelial cells of IBD patients, suggesting a role in epithelial homeostasis. Stimulation of ephrin-B signaling in ephrin- B1/2 expressing rat IEC-6-cells with recombinant EphB1-Fc resulted in a significant dose-dependent acceleration of wound closure. Furthermore, fluorescence microscopy showed that EphB1-Fc induced coordinated migration of wound edge cells is associated with enhanced formation of lamellipodial protrusions into the wound, increased actin stress fiber assembly and production of laminin at the wound edge. CONCLUSION: EphB/ephrin-B signaling might represent a novel protective mechanism that promotes intestinal epithelial wound healing, with potential impact on epithelial restitution in IBD.展开更多
Corticosteroids and immunomodulators have been the mainstay therapies for Crohn’s disease. Corticosteroids are highly effective to control symptoms in the short- term, but they are not effective in maintaining remiss...Corticosteroids and immunomodulators have been the mainstay therapies for Crohn’s disease. Corticosteroids are highly effective to control symptoms in the short- term, but they are not effective in maintaining remission, they heal the mucosa in a reduced proportion of cases, and long-time exposure is associated with an increased risk of infections and mortality. Immunomodulators, azathioprine and methotrexate, heal the mucosa in a higher proportion of patients that corticosteroids but their onset of action is slow and they benefit less than half of patients with Crohn’s disease. In the last decade, medical therapy for Crohn’s disease has experienced a remarkable change due to the introduction of biologic therapy, and particularly the use of anti-tumour necrosis factor-alpha agents. Infliximab, adalimumab, and certolizumab pegol have demonstrated efficacy for induction and maintenance of remission in active Crohn’s disease. These agents have raised the bar for what is a suitable symptomatic response in Crohn’s disease and modification of the natural history of the disease has become a major goal in the treatment of Crohn’s disease. There are several data in the literature that suggest that early use of biologic therapy and achievement of mucosal healing contribute to disease course modification. However, many questions on early biological therapy for Crohn’s disease remain still unanswered.展开更多
基金Supported by the Gennan Research Society (DFG-SFB 585/A8) and the Dr. Heinz Maurer Grant KFB 1.7
文摘AIM:Eph receptor tyrosine kinases and their membrane bound receptor-like ligands, the ephrins, represent a bi-directional cell-cell contact signaling system that directs epithelial movements in development. The meaning of this system in the adult human gut is unknown. We investigated the Eph/ephrin mRNA expression in the intestinal epithelium of healthy controls and patients with inflammatory bowel disease (IBD). METHODS: mRNA expression profiles of all Eph/ephrin family members in normal small intestine and colon were established by real-time RT-PCR. In addition, differential expression in IBD was investigated by cDNA array technology, and validated by both real-time RT-PCR and immunohistochemistry. Potential effects of enhanced EphB/ephrin-B signaling were analyzed in an in vitro IEC-6 cell scratch wound model. RESULTS: Human adult intestinal mucosa exhibits a complex pattern of Eph receptors and ephrins. Beside the known prominent co-expression of EphA2 and ephrinAl, we found abundantly co-expressed EphB2 and ephrin-B1/2. Interestingly, cDNA array data, validated by real-time PCR and immunohistochemistry, showed upregulation of ephrin-B2 in both perilesional and lesional intestinal epithelial cells of IBD patients, suggesting a role in epithelial homeostasis. Stimulation of ephrin-B signaling in ephrin- B1/2 expressing rat IEC-6-cells with recombinant EphB1-Fc resulted in a significant dose-dependent acceleration of wound closure. Furthermore, fluorescence microscopy showed that EphB1-Fc induced coordinated migration of wound edge cells is associated with enhanced formation of lamellipodial protrusions into the wound, increased actin stress fiber assembly and production of laminin at the wound edge. CONCLUSION: EphB/ephrin-B signaling might represent a novel protective mechanism that promotes intestinal epithelial wound healing, with potential impact on epithelial restitution in IBD.
文摘Corticosteroids and immunomodulators have been the mainstay therapies for Crohn’s disease. Corticosteroids are highly effective to control symptoms in the short- term, but they are not effective in maintaining remission, they heal the mucosa in a reduced proportion of cases, and long-time exposure is associated with an increased risk of infections and mortality. Immunomodulators, azathioprine and methotrexate, heal the mucosa in a higher proportion of patients that corticosteroids but their onset of action is slow and they benefit less than half of patients with Crohn’s disease. In the last decade, medical therapy for Crohn’s disease has experienced a remarkable change due to the introduction of biologic therapy, and particularly the use of anti-tumour necrosis factor-alpha agents. Infliximab, adalimumab, and certolizumab pegol have demonstrated efficacy for induction and maintenance of remission in active Crohn’s disease. These agents have raised the bar for what is a suitable symptomatic response in Crohn’s disease and modification of the natural history of the disease has become a major goal in the treatment of Crohn’s disease. There are several data in the literature that suggest that early use of biologic therapy and achievement of mucosal healing contribute to disease course modification. However, many questions on early biological therapy for Crohn’s disease remain still unanswered.
