Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro.

Riegler, Martin; Sedivy, Roland; Pothoulakis, Charalabos; Hamilton, Gerhard; Zacherl, Johannes; Bischof, G.; Cosentini, Enrico P.; Feil, W.; Schiessel, R; LaMont, J. Thomas

doi:10.1172/jci117885

Cited by 312 publications

(223 citation statements)

References 38 publications

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“…Unlike other actin-based structures, microvilli are uniquely refractory to the depolymerizing effects of cytochalasin or latrunculin. On the other hand, agents that impair Rho GTPase function, such as TxB have profound effects on microvillar structure (20). Treatment of MDCK-NHE3Ј 38HA3 cells with TxB altered their morphology, depleting the homogeneously sized microvilli seen in control cells and generating instead irregular ruffles and filopodia (Fig.…”

Section: Cytoskeletal Anchorage Accounts For the Limited Mobility Of mentioning

confidence: 99%

Rho GTPases dictate the mobility of the Na/H exchanger NHE3 in epithelia: Role in apical retention and targeting

Alexander

Furuya

Szászi

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Proximal tubular reabsorption of filtered sodium by the sodium͞ hydrogen exchanger isoform 3 (NHE3), located on the apical membrane, is fundamental to the maintenance of systemic volume and pH homeostasis. NHE3 is finely regulated by a variety of hormones and by changes in ionic composition and volume, likely requiring redistribution of the exchangers. We analyzed the subcellular distribution and dynamics of the exchangers by generating an epithelial line expressing NHE3 tagged with an exofacial epitope, which enabled us to monitor exchanger mobility and traffic in intact cells. Using determinations of fluorescence recovery after photobleaching in combination with dynamic measurements of subcellular distribution, we found that, in renal epithelial cells, NHE3 exists in four distinct subcompartments: a virtually immobile subpopulation that is retained on the apical membrane by interaction with the actin cytoskeleton in a manner that depends on the sustained activity of Rho GTPases; a mobile subpopulation on the apical membrane, which can be readily internalized; and two intracellular compartments that can be differentiated by their rate of exchange with the apical pool of NHE3. We provide evidence that detachment of the immobile fraction from its cytoskeletal anchorage leads to rapid internalization. These observations suggest that modulation of the mobile fraction of NHE3 on the apical membrane can alter the number of functional exchangers on the cell surface and, consequently, the rate of transepithelial ion transport. Regulation of the interaction of NHE3 with the actin cytoskeleton can therefore provide a new mode of regulation of sodium and hydrogen transport. fluorescence recovery after photobleaching ͉ pH regulation ͉ sodium proton exchange ͉ hypertension ͉ Madin-Darby canine kidney cells

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Section: Cytoskeletal Anchorage Accounts For the Limited Mobility Of mentioning

confidence: 99%

Rho GTPases dictate the mobility of the Na/H exchanger NHE3 in epithelia: Role in apical retention and targeting

Alexander

Furuya

Szászi

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…The cellular mechanism of toxin A involves glucosylation of a threonine residue at position 37 on Rho, Rac, and cdc42 (8), small GTP-binding proteins that regulate cell shape through modulation of the actin cytoskeleton. Monoglucosylation and inactivation of Rho proteins by the toxin causes severe cytoskeletal abnormalities in cultured and intact human colonocytes (9,10). However, the signal transduction pathways by which toxin A induces intestinal inflammation are not entirely known.…”

mentioning

confidence: 99%

Clostridium difficile Toxin A Regulates Inducible Cyclooxygenase-2 and Prostaglandin E2 Synthesis in Colonocytes via Reactive Oxygen Species and Activation of p38 MAPK

Kim

Rhee

Kokkotou

et al. 2005

Journal of Biological Chemistry

118

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“…difficile is the primary agent responsible for antibioticassociated diarrhea and pseudomembranous colitis after antibiotic therapy (20). C. difficile causes diarrhea and colitis by releasing two high-molecular-mass protein exotoxins, toxin A and B, with potent cytotoxic and enterotoxic properties in animal and human intestine (21). Injection of toxin A into ileal or colonic loops of anesthetized animals triggers mucosal neutrophil infiltration and increases fluid secretion and mucosal permeability 1-4 h after toxin A administration (22)(23)(24)(25).…”

mentioning

confidence: 99%

Corticotropin-releasing hormone (CRH) requirement inClostridium difficiletoxin A-mediated intestinal inflammation

Anton

Mykoniatis²,

Pan³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Clostridium difficile, the causative agent of antibiotic-associated colitis, mediates inflammatory diarrhea by releasing toxin A, a potent 308-kDa enterotoxin. Toxin A-induced inflammatory diarrhea involves many steps, including mucosal release of substance P (SP) corticotropin-releasing hormone (CRH) and neutrophil transmigration. Here we demonstrate that, compared with wild type, mice genetically deficient in CRH (Crh ؊/؊ ) have dramatically reduced ileal fluid secretion, epithelial cell damage, and neutrophil transmigration 4 h after intraluminal toxin A administration. This response is associated with diminished mucosal activity of the neutrophil enzyme myeloperoxidase compared with that of wildtype mice. In wild-type mice, toxin A stimulates an increase in intestinal SP content compared with buffer administration. In contrast, toxin A administration in Crh ؊/؊ mice fails to result in an increased SP content. Moreover, immunohistochemical experiments showed that CRH and SP are colocalized in some enteric nerves of wild-type mice, and this colocalization is more evident after toxin A administration. These results provide direct evidence for a major proinflammatory role for CRH in the pathophysiology of enterotoxin-mediated inflammatory diarrhea and indicate a SP-linked pathway.C orticotropin-releasing hormone (CRH), a 41-aa peptide, is a major peptide hormone that modulates the activity of the hypothalamic-pituitary-adrenal axis during stress, including inflammation (1-3). CRH mediates its effects by binding to its G protein-coupled receptor subtypes, CRH1 and CRH2 (4-6). CRH plays a dual role in the pathophysiology of inflammation. CRH secreted from the hypothalamus has indirect antiinflammatory effects via stimulation of glucocorticoid release, but CRH is also expressed peripherally, and its expression is increased in leukocytes, nerve fibers, and other cells involved in inflammatory reactions (7-12). Moreover, in vivo and in vitro studies indicate that CRH is a potent proinflammatory peptide (7,(12)(13)(14)(15).A limited number of studies indicate that CRH and its receptors play a role in the pathophysiology of intestinal inflammation. Thus, Van Tol et al. (11) found increased CRH expression in the rat cecum in colitis induced by injection of peptidoglycan-polysaccharide polymers. Increased expression of CRH-immunoreactive cells was also evident in the colonic mucosa of patients with inflammatory bowel disease (16). CRH gene expression is increased in hypothalamic neurons during colitis after intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid (17) and appears to play a protective role in the worsening of experimental colitis induced by stress (18). We have recently shown that expression of CRH as well as CRH1 and CRH2 was dramatically increased in mouse ileum shortly after intraluminal administration of Clostridium difficile toxin A (19). Moreover, experiments with CRH receptor antagonists indicate that CRH plays a proinflammatory role in toxin A-induced intestinal secretion and inflammatio...

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Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro.

Cited by 312 publications

References 38 publications

Rho GTPases dictate the mobility of the Na/H exchanger NHE3 in epithelia: Role in apical retention and targeting

Rho GTPases dictate the mobility of the Na/H exchanger NHE3 in epithelia: Role in apical retention and targeting

Clostridium difficile Toxin A Regulates Inducible Cyclooxygenase-2 and Prostaglandin E2 Synthesis in Colonocytes via Reactive Oxygen Species and Activation of p38 MAPK

Corticotropin-releasing hormone (CRH) requirement inClostridium difficiletoxin A-mediated intestinal inflammation

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