<big dropzone="etHRpI"><noframes id="7nEqvXqB"> Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil VSports app下载. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure V体育官网. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. .

. 2007 Dec 24;204(13):3067-76.
doi: 10.1084/jem.20071416. Epub 2007 Nov 26.

JAM-A regulates permeability and inflammation in the intestine in vivo

Mike G Laukoetter  1 , Porfirio Nava, Winston Y Lee, Eric A Severson, Christopher T Capaldo, Brian A Babbin, Ifor R Williams, Michael Koval, Eric Peatman, Jacquelyn A Campbell, Terence S Dermody, Asma Nusrat, Charles A Parkos
Affiliations

VSports手机版 - JAM-A regulates permeability and inflammation in the intestine in vivo

Mike G Laukoetter et al. J Exp Med. .

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. VSports手机版.

PubMed Disclaimer

"V体育官网" Figures

Figure 1.
Figure 1.
Increased colonic inflammation in JAM-A−/− mice. (A) Increased small lymphoid aggregates in JAM-A−/− mice. (B) Large lymphoid aggregates in JAM-A−/− mice identified as isolated lymphoid follicles. (C) Large, isolated submucosal lymphoid follicles observed only in JAM-A−/− mice. CD11c staining is shown in red. (D) Increased PMN in the colonic mucosa of JAM-A−/− mice. Bars, 40 μm. (E) MPO activity in the colonic mucosa of JAM-A−/− mice and littermate controls (n = 6). Horizontal bars represent the mean.
Figure 2.
Figure 2.
JAM-A deficiency results in enhanced intestinal permeability in vivo and in vitro. (A) TER of SK-CO15 cells after transient transfection with JAM-A siRNA. *, P< 0.05. (B) In vivo gastrointestinal permeability in control and JAM-A−/− mice 4 h after FITC-dextran gavage. Horizontal bars represent mean. (C) FD-4 flux across colonic mucosal sheets of WT and JAM-A−/− mice (n = 5 each). *, P < 0.05. Error bars in A and C represent the mean ± SEM. (D) Resistance across colonic mucosal sheets for JAM-A−/− mice and WT littermate controls (n = 5).
Figure 3.
Figure 3.
JAM-A deficiency results in altered claudin expression in vitro and in vivo. (A) Claudin protein expression profiles after JAM-A siRNA transfection in vitro. (B) Colonic mucosal claudin protein expression profiles in vivo from JAM-A−/− mice. (C) Densitometric analysis of claudin and occludin expression from Western blots obtained from WT and JAM-A−/− mice (n = 5 each). *, P < 0.05. (D–G) Immunofluorescence images of claudin-10 and -15, occludin, and claudin-2 expression in the colonic mucosa of WT and JAM-A−/− mice. ***, P < 0.0001. Error bars represent the mean ± SEM. Bars, 40 μM.
Figure 4.
Figure 4.
JAM-A deficiency increases susceptibility to DSS-induced colitis. (A) DAI. *, P < 0.05, increase in DSS treatment compared with mice plus water per os (po) beginning at day 2; **, P < 0.05, increase in JAM-A plus DSS treatment compared with WT and JAM+/− plus DSS starting at day 2. (B) Percent weight change. *, P < 0.05, DSS treatment compared with mice plus water po; **, P < 0.05, JAM-A plus DSS treatment compared with WT and JAM+/− plus DSS. (C) Colon weight/length ratio. *, P < 0.05 versus control mice; **, P < 0.05 versus WT plus DSS po. (D) Colonic MPO activity. *, P < 0.05 versus mice plus water po; **, P < 0.05 versus WT control mice. (E) Histology score. *, P < 0.05 versus water po; **, P < 0.05 versus WT plus DSS po. Error bars represent the mean ± SEM. (F) Colonic hematoxylin and eosin staining. Note the less crypt injury/ulceration and the abundance of goblet cells in JAM-A−/− mice compared with control (arrows). Bars: (left) 250 μm; (right) 50 μm.
Figure 5.
Figure 5.
Increased epithelial proliferation in the colonic mucosa of JAM-A−/− mice. (A) Immunofluorescence labeling profile for Ki-67 in JAM-A−/− and WT mice before and after treatment with DSS. Ki-67 is shown in green and nuclei are shown in blue. (B) Ki-67–positive cells (green) costained with the epithelial cell marker β-catenin (red) and cell nuclei (blue). The inset highlights individual Ki-67–positive epithelial cells. Bars, 40 μM. (C) Analysis of the percentage of proliferating epithelial cells (three tissue sections stained per animal; n = 5 per group; *, P < 0.05. Error bars represent the mean ± SEM.
See this image and copyright information in PMC

References

    1. Olson, T.S., B.K. Reuter, K.G. Scott, M.A. Morris, X.M. Wang, L.N. Hancock, T.L. Burcin, S.M. Cohn, P.B. Ernst, F. Cominelli, et al. 2006. The primary defect in experimental ileitis originates from a nonhematopoietic source. J. Exp. Med. 203:541–552. - PMC - PubMed
    1. Jump, R.L., and A.D. Levine. 2004. Mechanisms of natural tolerance in the intestine: implications for inflammatory bowel disease. Inflamm. Bowel Dis. 10:462–478. - PubMed
    1. Peeters, M., B. Geypens, D. Claus, H. Nevens, Y. Ghoos, G. Verbeke, F. Baert, S. Vermeire, R. Vlietinck, and P. Rutgeerts. 1997. Clustering of increased small intestinal permeability in families with Crohn's disease. Gastroenterology. 113:802–807. - PubMed
    1. Schmitz, H., C. Barmeyer, M. Fromm, N. Runkel, H.D. Foss, C.J. Bentzel, E.O. Riecken, and J.D. Schulzke. 1999. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology. 116:301–309. - PubMed
    1. Martin-Padura, I., S. Lostaglio, M. Schneemann, L. Williams, M. Romano, P. Fruscella, C. Panzeri, A. Stoppacciaro, L. Ruco, A. Villa, et al. 1998. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J. Cell Biol. 142:117–127. - PMC - PubMed

Publication types

MeSH terms