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Your search keyword '"Capaldo, Christopher T."' showing total 35 results
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35 results on '"Capaldo, Christopher T."'

1. Indoles from commensal bacteria extend healthspan

Author

Sonowal, Robert, Swimm, Alyson, Sahoo, Anusmita, Luo, Liping, Matsunaga, Yohei, Wu, Ziqi, Bhingarde, Jui A., Ejzak, Elizabeth A., Ranawade, Ayush, Qadota, Hiroshi, Powell, Domonica N., Capaldo, Christopher T., Flacker, Jonathan M., Jones, Rhienallt M., Benian, Guy M., and Kalman, Daniel

Published
2017

16. Annexin A1 Regulates Intestinal Mucosal Injury, Inflammation, and Repair1

Author

Babbin, Brian A., Laukoetter, Mike G., Nava, Porfirio, Koch, Stefan, Lee, Winston Y., Capaldo, Christopher T., Peatman, Eric, Severson, Eric A., Flower, Roderick J., Perretti, Mauro, Parkos, Charles A., and Nusrat, Asma

Subjects
Mice, Knockout, endocrine system, Mice, Inbred BALB C, Wound Healing, Dextran Sulfate, Colitis, Severity of Illness Index, Article, Mice, Animals, Female, Genetic Predisposition to Disease, Inflammation Mediators, Intestinal Mucosa, Annexin A1
Abstract

During mucosal inflammation, a complex array of proinflammatory and protective mechanisms regulates inflammation and severity of injury. Secretion of anti-inflammatory mediators is a mechanism that is critical in controlling inflammatory responses and promoting epithelial restitution and barrier recovery. AnxA1 is a potent anti-inflammatory protein that has been implicated to play a critical immune regulatory role in models of inflammation. Although AnxA1 has been shown to be secreted in intestinal mucosal tissues during inflammation, its potential role in modulating the injury/inflammatory response is not understood. In this study, we demonstrate that AnxA1-deficient animals exhibit increased susceptibility to dextran sulfate sodium (DSS)-induced colitis with greater clinical morbidity and histopathologic mucosal injury. Furthermore, impaired recovery following withdrawal of DSS administration was observed in AnxA1 (-/-) animals compared with wild-type (WT) control mice that was independent of inflammatory cell infiltration. Since AnxA1 exerts its anti-inflammatory properties through stimulation of ALX/FPRL-1, we explored the role of this receptor-ligand interaction in regulating DSS-induced colitis. Interestingly, treatment with an ALX/FPRL-1 agonist, 15-epi-lipoxin A4 reversed the enhanced sensitivity of AnxA1 (-/-) mice to DSS colitis. In contrast, 15-epi-lipoxin A4 did not significantly improve the severity of disease in WT animals. Additionally, differential expression of ALX/FPLR-1 in control and DSS-treated WT and AnxA1-deficient animals suggested a potential role for AnxA1 in regulating ALX/FPRL-1 expression under pathophysiological conditions. Together, these results support a role of endogenous AnxA1 in the protective and reparative properties of the intestinal mucosal epithelium.

Published
2008

19. Tight function zonula occludens-3 regulates cyclin D1-dependent cell proliferation

Author

Capaldo, Christopher T., Koch, Stefan, Kwon, Michael, Laur, Oskar, Parkos, Charles A., Nusrat, Asma, Capaldo, Christopher T., Koch, Stefan, Kwon, Michael, Laur, Oskar, Parkos, Charles A., and Nusrat, Asma

Abstract

Coordinated regulation of cell proliferation is vital for epithelial tissue homeostasis, and uncontrolled proliferation is a hallmark of carcinogenesis. A growing body of evidence indicates that epithelial tight junctions (TJs) play a role in these processes, although the mechanisms involved are poorly understood. In this study, we identify and characterize a novel plasma membrane pool of cyclin D1 with cell-cycle regulatory functions. We have determined that the zonula occludens (ZO) family of TJ plaque proteins sequesters cyclin D1 at TJs during mitosis, through an evolutionarily conserved class II PSD-95, Dlg, and ZO-1 (PDZ)-binding motif within cyclin D1. Disruption of the cyclin D1/ZO complex through mutagenesis or siRNA-mediated suppression of ZO-3 resulted in increased cyclin D1 proteolysis and G(0)/G(1) cell-cycle retention. This study highlights an important new role for ZO family TJ proteins in regulating epithelial cell proliferation through stabilization of cyclin D1 during mitosis.

Published
2011
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20. Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways

Author

Nava, Porfirio, Koch, Stefan, Laukoetter, Mike G., Lee, Winston Y., Kolegraff, Keli, Capaldo, Christopher T., Beeman, Neal, Addis, Caroline, Gerner-Smidt, Kirsten, Neumaier, Irmgard, Skerra, Arne, Li, Linheng, Parkos, Charles A., Nusrat, Asma, Nava, Porfirio, Koch, Stefan, Laukoetter, Mike G., Lee, Winston Y., Kolegraff, Keli, Capaldo, Christopher T., Beeman, Neal, Addis, Caroline, Gerner-Smidt, Kirsten, Neumaier, Irmgard, Skerra, Arne, Li, Linheng, Parkos, Charles A., and Nusrat, Asma

Abstract

Inflammatory cytokines have been proposed to regulate epithelial homeostasis during intestinal inflammation. We report here that interferon-gamma (IFN-gamma) regulates the crucial homeostatic functions of cell proliferation and apoptosis through serine-threonine protein kinase AKT-beta-catenin and Wingless-Int (Wnt)-beta-catenin signaling pathways. Short-term exposure of intestinal epithelial cells to IFN-gamma resulted in activation of beta-catenin through AKT, followed by induction of the secreted Wnt inhibitor Dkk1. Consequently, we observed an increase in Dkk1-mediated apoptosis upon extended IFN-gamma treatment and reduced proliferation through depletion of the Wnt coreceptor LRP6. These effects were enhanced by tumor necrosis factor-alpha (TNF-alpha), suggesting synergism between the two cytokines. Consistent with these results, colitis in vivo was associated with decreased beta-catenin-T cell factor (TCF) signaling, loss of plasma membrane-associated LRP6, and reduced epithelial cell proliferation. Proliferation was partially restored in IFN-gamma-deficient mice. Thus, we propose that IFN-gamma regulates intestinal epithelial homeostasis by sequential regulation of converging beta-catenin signaling pathways., Nava, Porfirio Koch, Stefan Laukoetter, Mike G Lee, Winston Y Kolegraff, Keli Capaldo, Christopher T Beeman, Neal Addis, Caroline Gerner-Smidt, Kirsten Neumaier, Irmgard Skerra, Arne Li, Linheng Parkos, Charles A Nusrat, Asma eng R01 DK059888-09/DK/NIDDK NIH HHS/ R01 DK079392/DK/NIDDK NIH HHS/ R01 DK061379-08/DK/NIDDK NIH HHS/ DK55679/DK/NIDDK NIH HHS/ R29 DK055679/DK/NIDDK NIH HHS/ T32 GM008169/GM/NIGMS NIH HHS/ DK72564/DK/NIDDK NIH HHS/ DK64399/DK/NIDDK NIH HHS/ R01 DK072564/DK/NIDDK NIH HHS/ R01 DK055679-12/DK/NIDDK NIH HHS/ DK53202/DK/NIDDK NIH HHS/ R24 DK064399/DK/NIDDK NIH HHS/ R24 DK064399-019003/DK/NIDDK NIH HHS/ DK59888/DK/NIDDK NIH HHS/ DK79392/DK/NIDDK NIH HHS/ R01 DK055679/DK/NIDDK NIH HHS/ R01 DK079392-07/DK/NIDDK NIH HHS/ R24 DK064399-019002/DK/NIDDK NIH HHS/ R01 DK061379/DK/NIDDK NIH HHS/ R01 DK059888/DK/NIDDK NIH HHS/ DK61379/DK/NIDDK NIH HHS/ R01 DK072564-15/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2010/03/23 06:00 Immunity. 2010 Mar 26;32(3):392-402. doi: 10.1016/j.immuni.2010.03.001. Epub 2010 Mar 18.

Published
2010
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21. Dkk-1 inhibits intestinal epithelial cell migration by attenuating directional polarization of leading edge cells

Author

Koch, Stefan, Capaldo, Christopher T., Samarin, Stanislav, Nava, Porfirio, Neumaier, Irmgard, Skerra, Arne, Sacks, David B., Parkos, Charles A., Nusrat, Asma, Koch, Stefan, Capaldo, Christopher T., Samarin, Stanislav, Nava, Porfirio, Neumaier, Irmgard, Skerra, Arne, Sacks, David B., Parkos, Charles A., and Nusrat, Asma

Abstract

Wnt signaling pathways regulate proliferation, motility, and survival in a variety of human cell types. Dickkopf-1 (Dkk-1) is a secreted Wnt antagonist that has been proposed to regulate tissue homeostasis in the intestine. In this report, we show that Dkk-1 is secreted by intestinal epithelial cells after wounding and that it inhibits cell migration by attenuating the directional orientation of migrating epithelial cells. Dkk-1 exposure induced mislocalized activation of Cdc42 in migrating cells, which coincided with a displacement of the polarity protein Par6 from the leading edge. Consequently, the relocation of the microtubule organizing center and the Golgi apparatus in the direction of migration was significantly and persistently inhibited in the presence of Dkk-1. Small interfering RNA-induced down-regulation of Dkk-1 confirmed that extracellular exposure to Dkk-1 was required for this effect. Together, these data demonstrate a novel role of Dkk-1 in the regulation of directional polarization of migrating intestinal epithelial cells, which contributes to the effect of Dkk-1 on wound closure in vivo., Koch, Stefan Capaldo, Christopher T Samarin, Stanislav Nava, Porfirio Neumaier, Irmgard Skerra, Arne Sacks, David B Parkos, Charles A Nusrat, Asma eng R01 DK079392/DK/NIDDK NIH HHS/ R29 DK055679/DK/NIDDK NIH HHS/ DK-72564/DK/NIDDK NIH HHS/ DK-055679/DK/NIDDK NIH HHS/ R01 DK072564/DK/NIDDK NIH HHS/ DK-61379/DK/NIDDK NIH HHS/ DK-79392/DK/NIDDK NIH HHS/ R01 DK055679/DK/NIDDK NIH HHS/ R01 DK061379/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural 2009/09/25 06:00 Mol Biol Cell. 2009 Nov;20(22):4816-25. doi: 10.1091/mbc.E09-05-0415. Epub 2009 Sep 23.

Published
2009
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28. Annexin A1 Regulates Intestinal Mucosal Injury, Inflammation, and Repair

Author

Babbin, Brian A., primary, Laukoetter, Mike G., additional, Nava, Porfirio, additional, Koch, Stefan, additional, Lee, Winston Y., additional, Capaldo, Christopher T., additional, Peatman, Eric, additional, Severson, Eric A., additional, Flower, Roderick J., additional, Perretti, Mauro, additional, Parkos, Charles A., additional, and Nusrat, Asma, additional

Published
2008
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29. JAM-A regulates permeability and inflammation in the intestine in vivo

Author

Laukoetter, Mike G., primary, Nava, Porfirio, additional, Lee, Winston Y., additional, Severson, Eric A., additional, Capaldo, Christopher T., additional, Babbin, Brian A., additional, Williams, Ifor R., additional, Koval, Michael, additional, Peatman, Eric, additional, Campbell, Jacquelyn A., additional, Dermody, Terence S., additional, Nusrat, Asma, additional, and Parkos, Charles A., additional

Published
2007
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33. Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways.

Author

Nava P, Koch S, Laukoetter MG, Lee WY, Kolegraff K, Capaldo CT, Beeman N, Addis C, Gerner-Smidt K, Neumaier I, Skerra A, Li L, Parkos CA, and Nusrat A

Subjects
Animals, Apoptosis, Cell Line, Cell Proliferation, Colitis genetics, Colitis immunology, Colitis metabolism, Colitis pathology, Epithelial Cells cytology, Epithelial Cells metabolism, Interferon-gamma deficiency, Interferon-gamma metabolism, Intestinal Mucosa metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Proto-Oncogene Proteins c-akt metabolism, Wnt Proteins metabolism, Epithelial Cells immunology, Homeostasis, Interferon-gamma immunology, Intestines immunology, Signal Transduction, beta Catenin metabolism
Abstract

Inflammatory cytokines have been proposed to regulate epithelial homeostasis during intestinal inflammation. We report here that interferon-gamma (IFN-gamma) regulates the crucial homeostatic functions of cell proliferation and apoptosis through serine-threonine protein kinase AKT-beta-catenin and Wingless-Int (Wnt)-beta-catenin signaling pathways. Short-term exposure of intestinal epithelial cells to IFN-gamma resulted in activation of beta-catenin through AKT, followed by induction of the secreted Wnt inhibitor Dkk1. Consequently, we observed an increase in Dkk1-mediated apoptosis upon extended IFN-gamma treatment and reduced proliferation through depletion of the Wnt coreceptor LRP6. These effects were enhanced by tumor necrosis factor-alpha (TNF-alpha), suggesting synergism between the two cytokines. Consistent with these results, colitis in vivo was associated with decreased beta-catenin-T cell factor (TCF) signaling, loss of plasma membrane-associated LRP6, and reduced epithelial cell proliferation. Proliferation was partially restored in IFN-gamma-deficient mice. Thus, we propose that IFN-gamma regulates intestinal epithelial homeostasis by sequential regulation of converging beta-catenin signaling pathways.

Published
2010
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34. Junctional adhesion molecule A interacts with Afadin and PDZ-GEF2 to activate Rap1A, regulate beta1 integrin levels, and enhance cell migration.

Author

Severson EA, Lee WY, Capaldo CT, Nusrat A, and Parkos CA

Subjects
Animals, Cell Line, Cell Membrane metabolism, Down-Regulation, Enzyme Activation, Epithelial Cells enzymology, Humans, Membrane Proteins metabolism, Mice, Models, Biological, Nerve Tissue Proteins metabolism, Phosphoproteins metabolism, Protein Binding, Receptors, Cell Surface, Signal Transduction, Zonula Occludens-1 Protein, Cell Adhesion Molecules metabolism, Cell Movement, Epithelial Cells cytology, Guanine Nucleotide Exchange Factors metabolism, Immunoglobulins metabolism, Integrin beta1 metabolism, Microfilament Proteins metabolism, rap1 GTP-Binding Proteins metabolism
Abstract

Junctional adhesion molecule-A (JAM-A) is a transmembrane tight junction protein that has been shown to regulate barrier function and cell migration through incompletely understood mechanisms. We have previously demonstrated that JAM-A regulates cell migration by dimerization of the membrane-distal immunoglobulin-like loop and a C-terminal postsynaptic density 95/disc-large/zona occludens (PDZ) binding motif. Disruption of dimerization resulted in decreased epithelial cell migration secondary to diminished levels of beta1 integrin and active Rap1. Here, we report that JAM-A is physically and functionally associated with the PDZ domain-containing molecules Afadin and PDZ-guanine nucleotide exchange factor (GEF) 2, but not zonula occludens (ZO)-1, in epithelial cells, and these interactions mediate outside-in signaling events. Both Afadin and PDZ-GEF2 colocalized and coimmunoprecipitated with JAM-A. Furthermore, association of PDZ-GEF2 with Afadin was dependent on the expression of JAM-A. Loss of JAM-A, Afadin, or PDZ-GEF2, but not ZO-1 or PDZ-GEF1, similarly decreased cellular levels of activated Rap1, beta1 integrin protein, and epithelial cell migration. The functional effects observed were secondary to decreased levels of Rap1A because knockdown of Rap1A, but not Rap1B, resulted in decreased beta1 integrin levels and reduced cell migration. These findings suggest that JAM-A dimerization facilitates formation of a complex with Afadin and PDZ-GEF2 that activates Rap1A, which regulates beta1 integrin levels and cell migration.

Published
2009
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35. JAM-A regulates permeability and inflammation in the intestine in vivo.

Author

Laukoetter MG, Nava P, Lee WY, Severson EA, Capaldo CT, Babbin BA, Williams IR, Koval M, Peatman E, Campbell JA, Dermody TS, Nusrat A, and Parkos CA

Subjects
Animals, Cell Line, Tumor, Epithelium embryology, Genetic Predisposition to Disease, Humans, Inflammation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Neutrophils metabolism, Permeability, Cell Adhesion Molecules physiology, Colon metabolism, Intestinal Mucosa metabolism, Receptors, Cell Surface physiology
Abstract

Recent evidence has linked intestinal permeability to mucosal inflammation, but molecular studies are lacking. Candidate regulatory molecules localized within the tight junction (TJ) include Junctional Adhesion Molecule (JAM-A), which has been implicated in the regulation of barrier function and leukocyte migration. Thus, we analyzed the intestinal mucosa of JAM-A-deficient (JAM-A(-/-)) mice for evidence of enhanced permeability and inflammation. Colonic mucosa from JAM-A(-/-) mice had normal epithelial architecture but increased polymorphonuclear leukocyte infiltration and large lymphoid aggregates not seen in wild-type controls. Barrier function experiments revealed increased mucosal permeability, as indicated by enhanced dextran flux, and decreased transepithelial electrical resistance in JAM-A(-/-) mice. The in vivo observations were epithelial specific, because monolayers of JAM-A(-/-) epithelial cells also demonstrated increased permeability. Analyses of other TJ components revealed increased expression of claudin-10 and -15 in the colonic mucosa of JAM-A(-/-) mice and in JAM-A small interfering RNA-treated epithelial cells. Given the observed increase in colonic inflammation and permeability, we assessed the susceptibility of JAM-A(-/-) mice to the induction of colitis with dextran sulfate sodium (DSS). Although DSS-treated JAM-A(-/-) animals had increased clinical disease compared with controls, colonic mucosa showed less injury and increased epithelial proliferation. These findings demonstrate a complex role of JAM-A in intestinal homeostasis by regulating epithelial permeability, inflammation, and proliferation.

Published
2007
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