Neutrophil migration across cultured intestinal epithelial monolayers is modulated by epithelial exposure to IFN-gamma in a highly polarized fashion.

Colgan, Sean P.; Parkos, Charles A.; Delp, C; Arnaout, M. Amin; Madara, James L.

doi:10.1083/jcb.120.3.785

Cited by 158 publications

(125 citation statements)

References 40 publications

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“…Thus, IFN-␥ may enhance the expression of ICAM-1, thereby inducing neutrophil transmigration. Furthermore, IFN-␥ can augment neutrophil transmigration through a monolayer of the human intestinal cell line, T84, in vitro (46). Taken collectively, locally produced IFN-␥ may enhance neutrophil transmigration directly and/or indirectly by enhancing chemokine production and ICAM-1 expression.…”

Section: Discussionmentioning

confidence: 99%

Essential Involvement of IFN-γ in Clostridium difficile Toxin A-Induced Enteritis

Ishida

Maegawa

Kondo

et al. 2004

The Journal of Immunology

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Clostridium difficile has emerged as the important causative agent of antibiotics-associated pesudomembranous colitis; especially its toxin A is presumed to be responsible for the colitis. We examined the pathophysiological roles of IFN-γ in toxin A-induced enteritis using IFN-γ knockout (KO) mice. When toxin A of C. difficile was injected into the ileal loops of BALB/c wild-type (WT) mice, massive fluid secretion, disruption of intestinal epithelial structure, and massive neutrophil infiltration developed within 4 h after the injection. IFN-γ protein was faintly detected in some CD3-positive lymphocytes in the lamina propria and submucosa of the ileum of untreated WT mice. On the contrary, at 2 and 4 h after toxin A injection, IFN-γ protein was detected in infiltrating neutrophils and to a lesser degree in CD3-positive lymphocytes. In the ileum of WT mice, toxin A treatment markedly enhanced the gene expression of TNF-α, macrophage inflammatory protein-1α and -2, KC, and ICAM-1 >2 h after treatment. In contrast, the histopathological changes were marginal, without enhanced fluid secretion in the ileum of toxin A-treated IFN-γ KO mice. Moreover, toxin A-induced gene expression of TNF-α, neutrophil chemotactic chemokines, and ICMA-1 was remarkably attenuated in IFN-γ KO mice. Furthermore, pretreatment of WT mice with a neutralizing anti-IFN-γ Ab prevented toxin A-induced enteritis. These observations indicate that IFN-γ is the crucial mediator of toxin A-induced acute enteritis and suggest that IFN-γ is an important molecular target for the control of C. difficile-associated pseudomembranous colitis.

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Section: Discussionmentioning

confidence: 99%

Essential Involvement of IFN-γ in Clostridium difficile Toxin A-Induced Enteritis

Ishida

Maegawa

Kondo

et al. 2004

The Journal of Immunology

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“…16,17,26 Nonetheless, recent studies have suggested that integrin-mediated adhesion may potentate PMN degranulation. 27 Because our transmigration assay uses MPO as a biochemical marker, we ruled out that these findings with wortmannin could result from differences in MPO content.…”

Section: Pi3k Inhibitors Promote Transmigrationmentioning

confidence: 99%

Phosphoinositide 3-kinase modulation of β3-integrin represents an endogenous “braking” mechanism during neutrophil transmatrix migration

Bruyninckx

Comerford

Lawrence

et al. 2001

Blood

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During episodes of inflammation, neutrophils (polymorphonuclear leukocytes[PMNs]) encounter subendothelial matrix substrates that may require additional signaling pathways as directives for movement through the extracellular space. Using an in vitro endothelial and epithelial model, inhibitors of phosphoinositide 3-kinase (PI3K) were observed to promote chemoattractant-stimulated migration by as much as 8 ؎ 0.3-fold. Subsequent studies indicated that PMNs respond in a similar manner to RGD-containing matrix substrates and that PMN-matrix interactions are potently inhibited by antibodies directed against ␤ 3 -but not ␤ 1 -integrin antibodies, and that PI3K inhibitors block ␤ 3 -integrin dependence. Biochemical analysis of intracellular ␤ 3 -integrin uncoupling by PI3K inhibitors revealed diminished ␤ 3 -integrin tyrosine phosphorylation and decreased association with p72 syk . Similarly, the p72 syk inhibitor piceatannol promoted PMN transmatrix migration, whereas HIV-tat peptide-facilitated loading of peptides corresponding to the ␤ 3 -integrin cytoplasmic tail identified the functional tyrosine residues for this activity. These data indicate that PI3K-regulated ␤ 3 -integrin represents a natural "braking" mechanism for PMNs during transit through the extracellular matrix. IntroductionMigration of neutrophils (polymorphonuclear leukocytes [PMNs ]) to sites of inflammation requires the coordinated interplay of soluble mediators, extracellular matrix ligands, and cell surface adhesion molecules. To subserve this function, PMNs must traverse endothelial cells lining the inner lumen of blood vessels. This process of transendothelial migration requires engagement and disengagement of a number of surface molecules and has been extensively studied. 1 After successful transendothelial migration, PMNs encounter subendothelial extracellular matrices in transit to inflammatory sites. Anchorage of cells to the extracellular matrix is mediated in part by integrins, a large family of heterodimeric cell surface proteins that mediate numerous cell functions, including motility, differentiation, and proliferation. 2 Integrin engagement of matrix ligand results in highly regulated signal transduction processes that cooperatively involve both "outside-in" and "insideout" pathways. 3 Importantly, integrin signaling can vary depending on the stimulus and on the cell type, 4 the molecular details of which are not fully understood at the present time.Recent studies have identified an important role for phosphoinositide-3-OH kinase (PI3K) in leukocyte migration. [5][6][7] The 4 known isoforms of PI3K are ␣, ␤, ␥, and ␦, and extracellular ligand coupling through membrane-localized G proteins generates the signaling molecule phosphatidylinositol 3,4,5-triphosphate. 8 PI3K coordinates a number of leukocyte effector functions, including leukocyte migration. [5][6][7]9 Although not fully understood at present, it appears that PI3K is central to stimulated chemotaxis. For instance, mice lacking the catalytic domain of leukocyte-specific PI3...

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“…To assay RAGE expression in T84 cells after inflammatory cytokine treatment, we incubated T84 monolayers with a culture medium containing TNF-␣ (20 ng/ml) or IFN-␥ (10 ng/ml), or a combination of the two, for 24, 48, and 72 h, respectively (34,35). After washing, the monolayers were fixed, blocked with 5% normal goat serum or BSA, followed by incubation with anti-RAGE Abs and labeling with Alexa Fluor-conjugated secondary Abs.…”

Section: Cytokine Treatment and Rage Measurementmentioning

confidence: 99%

“…To test whether RAGE plays a role in intestinal inflammation, we examined RAGE expression in intestinal epithelial monolayers treated with or without proinflammatory cytokines. In these experiments, T84 monolayers were cultured in the presence or absence of TNF-␣ and/or IFN-␥ for various time intervals (34,35), and the expression of RAGE in T84 cells was analyzed by immunofluorescence staining. We observed that RAGE expression along the lateral membranes of T84 cells was significantly increased after treatment with either TNF-␣ or/and IFN-␥.…”

Section: The Expression Of Rage Is Up-regulated Under Inflammatory Comentioning

confidence: 99%

Receptor for Advanced Glycation Endproducts Mediates Neutrophil Migration across Intestinal Epithelium

Zen

Chen

et al. 2007

The Journal of Immunology

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Receptor for advanced glycation endproducts (RAGE) is an Ig superfamily cell surface receptor that interacts with a diverse array of ligands associated with inflammatory responses. In this study, we provide evidence demonstrating that RAGE is involved in inflammatory responses in the intestines. We showed that RAGE is expressed in intestinal epithelial cells, primarily concentrated at the lateral membranes close to the apical cell junction complexes. Although RAGE expression was low in epithelium under normal conditions, this protein was up-regulated after treatment with the inflammatory cytokines IFN-γ and/or TNF-α. RAGE expression was also elevated in colon tissue samples from patients with inflammatory bowel diseases. Using in vitro transmigration assays, we found that RAGE mediates neutrophil (polymorphonuclear leukocytes (PMN)) adhesion to, and subsequent migration across, intestinal epithelial monolayers. This activity appears to be mediated by the binding of RAGE to the PMN-specific β2 integrin CD11b/CD18. Thus, these results provide a novel mechanism for the regulation of PMN transepithelial migration and may suggest a new therapeutic target for intestinal inflammation.

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Neutrophil migration across cultured intestinal epithelial monolayers is modulated by epithelial exposure to IFN-gamma in a highly polarized fashion.

Cited by 158 publications

References 40 publications

Essential Involvement of IFN-γ in Clostridium difficile Toxin A-Induced Enteritis

Essential Involvement of IFN-γ in Clostridium difficile Toxin A-Induced Enteritis

Phosphoinositide 3-kinase modulation of β3-integrin represents an endogenous “braking” mechanism during neutrophil transmatrix migration

Receptor for Advanced Glycation Endproducts Mediates Neutrophil Migration across Intestinal Epithelium

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