Tumor necrosis factor regulates intestinal epithelial cell migration by receptor-dependent mechanisms

2003 ◽  
Vol 284 (4) ◽  
pp. C953-C961 ◽  
Author(s):  
Julissa Corredor ◽  
Fang Yan ◽  
Christopher C. Shen ◽  
Wei Tong ◽  
Sutha K. John ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Necrosis Factor ◽  
Epithelial Cell ◽  
Tumor Necrosis ◽  
Intestinal Epithelial Cell ◽  
Wound Closure ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Epithelial Cell Migration ◽  
Necrosis Factor

Altered mucosal integrity and increased cytokine production, including tumor necrosis factor (TNF), are the hallmarks of inflammatory bowel disease (IBD). In this study, we addressed the role of TNF receptors (TNFR) on intestinal epithelial cell migration in an in vitro wound closure model. With mouse TNFR1 or TNFR2 knockout intestinal epithelial cells, gene transfection, and pharmacological inhibitors, we show a concentration-dependent receptor-mediated regulation of intestinal cell migration by TNF. A physiological TNF level (1 ng/ml) enhances migration through TNFR2, whereas a pathological level (100 ng/ml) inhibits wound closure through TNFR1. Increased rate of wound closure by TNFR2 or inhibition by TNFR1 cannot be explained by either increased proliferation or apoptosis, respectively. Furthermore, inhibiting Src tyrosine kinase decreases TNF-induced focal adhesion kinase (FAK) tyrosine phosphorylation and cellular migration. We therefore conclude that TNFR2 activates a novel Src-regulated pathway involving FAK tyrosine phosphorylation that enhances migration of intestinal epithelial cells.

scholarly journals Tumor necrosis factor-α represses the expression of NHE2 through NF-κB activation in intestinal epithelial cell model, C2BBe1

2011 ◽  
Vol 17 (3) ◽  
pp. 720-731 ◽  
Author(s):  
Ruhul Amin ◽  
Temitope Orenuga ◽  
Sangeeta Tyagi ◽  
Pradeep K. Dudeja ◽  
Krishnamurthy Ramaswamy ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Epithelial Cell ◽  
Tumor Necrosis ◽  
Intestinal Epithelial Cell ◽  
Tumor Necrosis Factor Α ◽  
Cell Model ◽  
Intestinal Epithelial ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals Tumor Necrosis Factor-α and Apoptosis Signal-Regulating Kinase 1 Control Reactive Oxygen Species Release, Mitochondrial Autophagy and C-Jun N-Terminal Kinase/P38 Phosphorylation During Necrotizing Enterocolitis

2009 ◽  
Vol 2 (5) ◽  
pp. 297-306 ◽  
Author(s):  
Naira Baregamian ◽  
Jun Song ◽  
C. Eric Bailey ◽  
John Papaconstantinou ◽  
B. Mark Evers ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Mitochondrial Dysfunction ◽  
Tumor Necrosis ◽  
Intestinal Epithelial Cell ◽  
Intestinal Epithelial Cells ◽  
Oxygen Species ◽  
Intestinal Epithelial ◽  
Epithelial Cell Apoptosis ◽  
Necrosis Factor

Background: Oxidative stress and inflammation may contribute to the disruption of the protective gut barrier through various mechanisms; mitochondrial dysfunction resulting from inflammatory and oxidative injury may potentially be a significant source of apoptosis during necrotizing enterocolitis (NEC). Tumor necrosis factor (TNF)α is thought to generate reactive oxygen species (ROS) and activate the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 pathway. Hence, the focus of our study was to examine the effects of TNFα/ROs on mitochondrial function, ASK1-JNK/p38 cascade activation in intestinal epithelial cells during NEC.Results: We found (a) abundant tissue TNFα and ASK1 expression throughout all layers of the intestine in neonates with NEC, suggesting that TNFα/ASK1 may be a potential source (indicators) of intestinal injury in neonates with NEC; (b) TNFα-induced rapid and transient activation of JNK/p38 apoptotic signaling in all cell lines suggests that this may be an important molecular characteristic of NEC; (c) TNFα-induced rapid and transient ROs production in RIe-1 cells indicates that mitochondria are the predominant source of ROS, demonstrated by significantly attenuated response in mitochondrial DNA-depleted (RIE-1-ρ°) intestinal epithelial cells; (d) further studies with mitochondria-targeted antioxidant PBN supported our hypothesis that effective mitochondrial ROS trapping is protective against TNFα/ROs-induced intestinal epithelial cell injury; (e) TNFα induces significant mitochondrial dysfunction in intestinal epithelial cells, resulting in increased production of mtROS, drop in mitochondrial membrane potential (MMP) and decreased oxygen consumption; (f) although the significance of mitochondrial autophagy in NEC has not been unequivocally shown, our studies provide a strong preliminary indication that TNFα/ROs-induced mitochondrial autophagy may play a role in NeC, and this process is a late phenomenon.Methods: Paraffin-embedded intestinal sections from neonates with NEC and non-inflammatory condition of the gastrointestinal tract undergoing bowel resections were analyzed for TNFα and ASK1 expression. Rat (RIE-1) and mitochondrial DNA-depleted (RIE-1-ρ°) intestinal epithelial cells were used to determine the effects of TNFα on mitochondrial function.Conclusions: Our findings suggest that TNFα induces significant mitochondrial dysfunction and activation of mitochondrial apoptotic responses, leading to intestinal epithelial cell apoptosis during NeC. Therapies directed against mitochondria/ROS may provide important therapeutic options, as well as ameliorate intestinal epithelial cell apoptosis during NeC.

Epidermal growth factor stimulates Rac activation through Src and phosphatidylinositol 3-kinase to promote colonic epithelial cell migration

2008 ◽  
Vol 294 (1) ◽  
pp. G276-G285 ◽  
Author(s):  
Rebecca S. Dise ◽  
Mark R. Frey ◽  
Robert H. Whitehead ◽  
D. Brent Polk
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Epithelial Cell ◽  
Intestinal Epithelial Cell ◽  
Wound Closure ◽  
Intestinal Epithelial ◽  
Phosphatidylinositol 3 Kinase ◽  
Epithelial Cell Migration ◽  
Wound Margin ◽  
Epidermal Growth

Regulated intestinal epithelial cell migration plays a key role in wound healing and maintenance of a healthy gastrointestinal tract. Epidermal growth factor (EGF) stimulates cell migration and wound closure in intestinal epithelial cells through incompletely understood mechanisms. In this study we investigated the role of the small GTPase Rac in EGF-induced cell migration using an in vitro wound-healing assay. In mouse colonic epithelial (MCE) cell lines, EGF-stimulated wound closure was accompanied by a doubling of the number of cells containing lamellipodial extensions at the wound margin, increased Rac membrane translocation in cells at the wound margin, and rapid Rac activation. Either Rac1 small interfering (si)RNA or a Rac1 inhibitor completely blocked EGF-stimulated wound closure. Whereas EGF failed to activate Rac in colon cells from EGF receptor (EGFR) knockout mice, stable expression of wild-type EGFR restored EGF-stimulated Rac activation and migration. Pharmacological inhibition of either phosphatidylinositol 3-kinase (PI3K) or Src family kinases reduced EGF-stimulated Rac activation. Cotreatment of cells with both inhibitors completely blocked EGF-stimulated Rac activation and localization to the leading edge of cells and lamellipodial extension. Our results present a novel mechanism by which the PI3K and Src signaling cascades cooperate to activate Rac and promote intestinal epithelial cell migration downstream of EGFR.

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