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Interferon-gamma Inhibits Intestinal Restitution by Preventing Gap Junction Communication Between Enterocytes

 

Enterocytes expressed connexin 43 in vitro and in vivo, and exchanged fluorescent dye via gap junctions. Gap junction inhibition significantly reduced enterocyte migration in vitro and in vivo. NEC was associated with IFN release and loss of enterocyte connexin 43 expression. IFN inhibited enterocyte migration by reducing gap junction communication through the dephosphorylation and internalization of connexin 43. Gap junction inhibition significantly increased NEC severity, whereas reversal of the inhibitory effects of IFN on gap junction communication restored enterocyte migration after IFN exposure. Strikingly, IFN(-/-) mice were protected from the development of NEC, and showed restored connexin 43 expression and intestinal restitution. Thus, we demonstrated that IFN inhibits enterocyte migration by preventing interenterocyte gap junction communication. Connexin 43 loss may provide insights into the development of NEC, in which restitution is impaired.

Experimental NEC is associated with impaired expression of Cx43. (A) NEC (“NEC”) was induced in 10-day-old Swiss-Webster mice using a combination of gavaged formula and hypoxia, while control animals were allowed to breast feed (see the Materials and Methods section). The expression of Cx43 by SDS-PAGE in mucosal scrapings obtained from the terminal ileum is shown, along with the reprobed immunoblot against actin to assess for protein loading. (B–C) Representative gross images of the small intestine obtained from freshly sacrificed control (B) and NEC (C) animals are shown. (D) Serum IL-6 concentration in control animals (“Ctl”), animals with NEC (“NEC”), animals that had been injected with oleamide (5 mg/kg) for each of the 4 days of the NEC induction (“NEC   Olm”), and animals injected with oleamide alone (5 mg/kg/ day for 4 days). *P  .05 vs control; **P.05 vs NEC. (E–J) Samples from the terminal ileum from control mice (E, G, H) and those with NEC (F, I, J) were immunostained with antibodies against Cx43 (green) and the nuclear marker Draq-5 (red). Representative confocal micrographs are shown at low magnification (E, F), in which dotted lines reflect regions at higher of representative villi and crypts (G–J). Representative of 5 separate experiments. Arrows indicate location of gap junctions.

Authors
Leaphart CL, Qureshi F, Cetin S, Li J, Dubowski T, Baty C, Beer-Stolz D, Guo F, Murray SA, Hackam DJ
Gastroenterology
2007 June

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January 19, 2011
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Last Update
January 19, 2011
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