5'-adenosine monophosphate is the neutrophil-derived paracrine factor that elicits chloride secretion from T84 intestinal epithelial cell monolayers.

Madara, James L.; Patapoff, Thomas W.; Gillece-Castro, Beth; Colgan, Sean P.; Parkos, Charles A.; Delp, C; Mrsny, Randall J.

doi:10.1172/jci116462

Cited by 272 publications

(202 citation statements)

References 15 publications

(16 reference statements)

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“…Recent studies have revealed that when coincubated with endothelia or epithelia, neutrophils release micromolar concentrations of 5Ј-AMP (4,7). 5Ј-AMP is rapidly converted to adenosine (via surface-expressed CD73), and adenosine liberated in this fashion directly activates surface adenosine A 2B receptors (4,7,10) and promotes endothelial barrier function through elevation of intracellular cAMP (4,11).…”

mentioning

confidence: 99%

Regulation of Endothelial CD73 by Adenosine: Paracrine Pathway for Enhanced Endothelial Barrier Function

Narravula

Lennon

Mueller

et al. 2000

The Journal of Immunology

109

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During episodes of inflammation, multiple cell types release adenine nucleotides in the form of ATP, ADP, 5′-AMP, and adenosine. In particular, following activation, polymorphonuclear leukocytes release larger quantities of 5′-AMP. Extracellular 5′-AMP is metabolized to adenosine by surface-expressed 5′-ectonucleotidase (CD73). Adenosine liberated by this process activates surface adenosine A2B receptors, results in endothelial junctional reorganization, and promotes barrier function. We hypothesized that adenosine signaling to endothelia provides a paracrine loop for regulated expression of CD73 and enhanced endothelial barrier function. Using an in vitro microvascular endothelial model, we investigated the influence of 5′-AMP; adenosine; and adenosine analogues on CD73 transcription, surface expression, and function. Initial experiments revealed that adenosine and adenosine analogues induce CD73 mRNA (RT-PCR), surface expression (immunoprecipitation of surface biotinylated CD73), and function (HPLC analysis of etheno-AMP conversion to ethenoadenosine) in a time- and concentration-dependent fashion. Subsequent studies revealed that similar exposure conditions increase surface protein through transcriptional induction of CD73. Analysis of DNA-binding activity by EMSA identified a functional role for CD73 cAMP response element and, moreover, indicated that multiple cAMP agonists induce transcriptional activation of functional CD73. Induced CD73 functioned to enhance 5′-AMP-mediated promotion of endothelial barrier (measured as a paracellular flux of 70-kDa FITC-labeled tracer). These results provide an example of transcriptional induction of enzyme (CD73) by enzymatic product (adenosine) and define a paracrine pathway for the regulated expression of vascular endothelial CD73 and barrier function.

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mentioning

confidence: 99%

Regulation of Endothelial CD73 by Adenosine: Paracrine Pathway for Enhanced Endothelial Barrier Function

Narravula

Lennon

Mueller

et al. 2000

The Journal of Immunology

109

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“…Diarrhea has been attributed both to villus atrophy-associated malabsorption and to mucosal inflammation-induced alteration in intestinal water and electrolyte transport. Neutrophils are a source of mediators, including reactive oxygen metabolites (4), TNF-␣ (17), 5Ј-AMP (24), and prostaglandins (1,2,4,12), that may directly or indirectly promote epithelial secretion and diarrhea in C. parvum infection. Neutrophil depletion of C. parvum-infected piglets had no effect on clinical severity of diarrhea or epithelial Cl Ϫ secretion, suggesting that mediators derived from or stimulated by neutrophils do not play a significant role in the genesis of diarrhea in the infection.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils Do Not Mediate the Pathophysiological Sequelae of Cryptosporidium parvum Infection in Neonatal Piglets

Zadrozny¹,

Stauffer²,

Armstrong³

et al. 2006

Infect Immun

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Cryptosporidium parvum is a minimally invasive protozoal pathogen of intestinal epithelium that results in villus atrophy, mucosal lipid peroxidation, diarrhea, and diminished barrier function. Influx of neutrophils is a consistent feature of human and animal cryptosporidiosis, and yet their contribution to the pathological sequelae of infection has not been investigated. Accordingly, we used an established neonatal piglet model of C. parvum infection to examine the role of neutrophils in disease pathogenesis by inhibiting their recruitment and activation in vivo using a monoclonal anti-CD18 antibody. Infected piglets were treated daily with anti-CD18 or isotype control immunoglobulin G and euthanized at peak infection, at which time neutrophil infiltrates, lipid peroxidation, severity of infection, and intestinal barrier function were quantified. C. parvum infection resulted in a significant increase in mucosal neutrophil myeloperoxidase activity that was prevented by treatment of piglets with anti-CD18 antibody. Neutrophil recruitment was dependent on mucosal superoxide formation (prevented by treatment of infected piglets with superoxide dismutase). Neutrophils did not contribute to peroxynitrite formation or peroxidative injury of C. parvum-infected mucosa and had no impact on the severity of epithelial infection, villus atrophy, or diarrhea. The presence of neutrophils in C. parvuminfected mucosa was associated with enhanced barrier function that could not be attributed to mucosal elaboration of prostaglandins or stimulation of their synthesis. These studies are the first to demonstrate that neutrophilic inflammation arising in response to infection by a noninvasive epithelial pathogen results in physiologic rather than pathological effects in vivo.

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“…64 At the apical surface of IECs, 5 0 ectonucleotidase (CD73) converts 5 0 AMP into adenosine. Adenosine then interacts in a paracrine manner with the A2b adenosine receptor, which by its association with G-protein as, indirectly activates adenylyl cyclase.…”

Section: Disruption Of Epithelial Barrier Structure and Functionmentioning

confidence: 99%

“…Adenosine then interacts in a paracrine manner with the A2b adenosine receptor, which by its association with G-protein as, indirectly activates adenylyl cyclase. 64,65 The subsequent increase in cAMP results in the activation of PKA and CFTR, promoting Cl À secretion and enhancing luminal movement of water. 64,65 In addition, another study showed that EPEC is able to induce the cellular release and rapid breakdown of ATP into adenine nucleotides and adenosine, feeding into the earlier described signaling cascade.…”

Section: Disruption Of Epithelial Barrier Structure and Functionmentioning

confidence: 99%

“…64,65 The subsequent increase in cAMP results in the activation of PKA and CFTR, promoting Cl À secretion and enhancing luminal movement of water. 64,65 In addition, another study showed that EPEC is able to induce the cellular release and rapid breakdown of ATP into adenine nucleotides and adenosine, feeding into the earlier described signaling cascade. 66 The inflammatory response associated with EPEC is associated with an increase in proinflammatory cytokines, such as TNFa, interferon (IFN) g, and IL-1b, in the infected mucosa.…”

Section: Disruption Of Epithelial Barrier Structure and Functionmentioning

confidence: 99%

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The role of epithelial malfunction in the pathogenesis of enteropathogenic E. coli-induced diarrhea

Lapointe

O'Connor

Buret

2009

Laboratory Investigation

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The homeostatic balance of the gastrointestinal tract relies on a single layer of epithelial cells, which assumes both digestive and protective functions. Enteric pathogens, including enteropathogenic Escherichia coli (EPEC), have evolved numerous mechanisms to disrupt basic intestinal epithelial functions, promoting the development of gastrointestinal disorders. Despite its non-invasive nature, EPEC inflicts severe damage to the intestinal mucosa, including the dysregulation of water and solute transport and the disruption of epithelial barrier structure and function. Despite the high prevalence and morbidity of disease caused by EPEC infections, the etiology of its pathogenesis remains incompletely understood. This review integrates the newest findings on EPEC-epithelial interactions with established mechanisms of disease in an attempt to give a comprehensive understanding of the cellular processes whereby this common pathogen may cause diarrheal illness.

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5'-adenosine monophosphate is the neutrophil-derived paracrine factor that elicits chloride secretion from T84 intestinal epithelial cell monolayers.

Cited by 272 publications

References 15 publications

Regulation of Endothelial CD73 by Adenosine: Paracrine Pathway for Enhanced Endothelial Barrier Function

Regulation of Endothelial CD73 by Adenosine: Paracrine Pathway for Enhanced Endothelial Barrier Function

Neutrophils Do Not Mediate the Pathophysiological Sequelae of Cryptosporidium parvum Infection in Neonatal Piglets

The role of epithelial malfunction in the pathogenesis of enteropathogenic E. coli-induced diarrhea

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