Intestinal Epithelial Cell Apoptosis following Cryptosporidium parvum Infection

ABSTRACT Cryptosporidium parvum induces moderate levels of apoptosis of cultured human intestinal epithelial cells, which are maximal at 24 h after infection. Apoptosis is further increased inC. parvum-infected cells by inhibition of NF-κB. C. parvum infection also attenuates epithelial apoptosis induced by strongly proapoptotic agents. The data suggest C. parvumhas developed strategies to limit apoptosis in order to facilitate its growth and maturation in the early period after epithelial cell infection.

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Intestinal epithelial cell apoptosis following Cryptosporidium parvum infection

Gastroenterology ◽

10.1016/s0016-5085(00)83393-4 ◽

2000 ◽

Vol 118 (4) ◽

pp. A325

Author(s):

Declan F. McCole ◽

Lars Eckmann ◽

Fabrice Laurent ◽

Martin F. Kagnoff

Keyword(s):

Epithelial Cell ◽

Cryptosporidium Parvum ◽

Cell Apoptosis ◽

Intestinal Epithelial Cell ◽

Intestinal Epithelial ◽

Epithelial Cell Apoptosis

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Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection

Journal of Virology ◽

10.1128/jvi.02062-17 ◽

2018 ◽

Vol 92 (10) ◽

Cited By ~ 12

Author(s):

Judy J. Brown ◽

Sarah P. Short ◽

Jennifer Stencel-Baerenwald ◽

Kelly Urbanek ◽

Andrea J. Pruijssers ◽

...

Keyword(s):

Celiac Disease ◽

Epithelial Cell ◽

Cell Apoptosis ◽

Oral Tolerance ◽

Intestinal Epithelial Cell ◽

Intestinal Epithelial Cells ◽

Enteric Infection ◽

Intestinal Epithelial ◽

Epithelial Cell Apoptosis ◽

Induced Apoptosis

ABSTRACTSeveral viruses induce intestinal epithelial cell death during enteric infection. However, it is unclear whether proapoptotic capacity promotes or inhibits replication in this tissue. We infected mice with two reovirus strains that infect the intestine but differ in the capacity to alter immunological tolerance to new food antigen. Infection with reovirus strain T1L, which induces an inflammatory immune response to fed antigen, is prolonged in the intestine, whereas T3D-RV, which does not induce this response, is rapidly cleared from the intestine. Compared with T1L, T3D-RV infection triggered apoptosis of intestinal epithelial cells and subsequent sloughing of dead cells into the intestinal lumen. We conclude that the infection advantage of T1L derives from its capacity to subvert host restriction by epithelial cell apoptosis, providing a possible mechanism by which T1L enhances inflammatory signals during antigen feeding. Using a panel of T1L × T3D-RV reassortant viruses, we identified the viral M1 and M2 gene segments as determinants of reovirus-induced apoptosis in the intestine. Expression of the T1L M1 and M2 genes in a T3D-RV background was sufficient to limit epithelial cell apoptosis and enhance viral infection to levels displayed by T1L. These findings define additional reovirus gene segments required for enteric infection of mice and illuminate the antiviral effect of intestinal epithelial cell apoptosis in limiting enteric viral infection. Viral strain-specific differences in the capacity to infect the intestine may be useful in identifying viruses capable of ameliorating tolerance to fed antigen in autoimmune conditions like celiac disease.IMPORTANCEAcute viral infections are thought to be cleared by the host with few lasting consequences. However, there may be much broader and long-lasting effects of viruses on immune homeostasis. Infection with reovirus, a common, nonpathogenic virus, triggers inflammation against innocuous food antigens, implicating this virus in the development of celiac disease, an autoimmune intestinal disorder triggered by exposure to dietary gluten. Using two reovirus strains that differ in the capacity to abrogate oral tolerance, we found that strain-specific differences in the capacity to replicate in the intestine inversely correlate with the capacity to induce apoptotic death of intestinal epithelial cells, providing a host-mediated process to restrict intestinal infection. This work contributes new knowledge about virus-host interactions in the intestine and establishes a foundation for future studies to define mechanisms by which viruses break oral tolerance in celiac disease.

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Iron chelation acutely stimulates fetal human intestinal cell production of IL-6 and VEGF while decreasing HGF: the roles of p38, ERK, and JNK MAPK signaling

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00502.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. G958-G963 ◽

Cited By ~ 17

Author(s):

Troy A. Markel ◽

Paul R. Crisostomo ◽

Meijing Wang ◽

Christine M. Herring ◽

Tim Lahm ◽

...

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

P38 Mapk ◽

Intestinal Epithelial Cell ◽

Intestinal Epithelial Cells ◽

Iron Chelation ◽

Intestinal Epithelial ◽

Cell Production ◽

Human Intestinal Epithelial Cells ◽

Tnf Α

Bacteria have developed mechanisms to sequester host iron via chelators such as deferoxamine (DFO). Interestingly, DFO has been shown to stimulate acute intestinal epithelial cell inflammatory cytokine production in the absence of bacteria; however, this mechanism has not been elucidated. Intestinal epithelial cell production of IL-6 and TNF-α is elevated in various gastrointestinal pathologies, including acute intestinal ischemia. Similarly, VEGF and HGF are essential to intestinal epithelial cell integrity. Therapeutic strategies that decrease IL-6 and TNF-α while increasing VEGF and HGF therefore have theoretical appeal. We hypothesized that 1) fetal human intestinal epithelial cells acutely produce increased IL-6, TNF-α, VEGF, and HGF during iron chelation and 2) the MAPK pathway mediates these effects. Fetal human intestinal epithelial cells were stimulated by iron chelation (1 mM DFO) with and without p38 MAPK, ERK, or JNK inhibition. Supernatants were harvested after 24 h of incubation, and IL-6, TNF-α, VEGF, and HGF levels were quantified by ELISA. Activation of MAPK pathways was confirmed by Western blot analysis. DFO stimulation resulted in a significant increase in epithelial cell IL-6 and VEGF production while yielding a decrease in HGF production ( P < 0.05). Unexpectedly, TNF-α was not detectable. p38 MAPK, ERK, and JNK inhibition significantly decreased IL-6, VEGF, and HGF production ( P < 0.05). In conclusion, DFO acutely increases fetal human intestinal epithelial cell IL-6 and VEGF expression while causing an unexpected decrease in HGF expression and no detectable TNF-α production. Furthermore, chelator-induced intestinal epithelial cell cytokine expression depends on p38, ERK, and JNK MAPK pathways.

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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

Oxidative Medicine and Cellular Longevity ◽

10.4161/oxim.2.5.9541 ◽

2009 ◽

Vol 2 (5) ◽

pp. 297-306 ◽

Cited By ~ 84

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.

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