HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 294/1/G109    most recent 00331.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Anand, R. J. Articles by Hackam, D. J. Search for Related Content PubMed PubMed Citation Articles by Anand, R. J. Articles by Hackam, D. J.

INFLAMMATION/IMMUNITY/MEDIATORS

Activated macrophages inhibit enterocyte gap junctions via the release of nitric oxide

¹Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh and University of Pittsburgh; ²Department of Cell Biology and Physiology, University of Pittsburgh; ³Center for Biological Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 21 July 2007 ; accepted in final form 28 October 2007

Enterocytes exist in close association with tissue macrophages, whose activation during inflammatory processes leads to the release of nitric oxide (NO). Repair from mucosal injury requires the migration of enterocytes into the mucosal defect, a process that requires connexin43 (Cx43)-mediated gap junction communication between adjacent enterocytes. Enterocyte migration is inhibited during inflammatory conditions including necrotizing enterocolitis, in part, through impaired gap junction communication. We now hypothesize that activated macrophages inhibit gap junctions of adjacent enterocytes and seek to determine whether NO release from macrophages was involved. Using a coculture system of enterocytes and macrophages, we now demonstrate that "activation" of macrophages with lipopolysaccharide and interferon reduces the phosphorylation of Cx43 in adjacent enterocytes, an event known to inhibit gap junction communication. The effects of macrophages on enterocyte gap junctions could be reversed by treatment of macrophages with the inducible nitric oxide synthase (iNOS) inhibitor L-Lysine -acetamidine hydrochloride (L-NIL) and by incubation with macrophages from iNOS^–/– mice, implicating NO in the process. Activated macrophages also caused a NO-dependent redistribution of connexin43 in adjacent enterocytes from the cell surface to an intracellular location, further suggesting NO release may inhibit gap junction function. Treatment of enterocytes with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) markedly inhibited gap junction communication as determined using single cell microinjection of the gap junction tracer Lucifer yellow. Strikingly, activated macrophages inhibited enterocyte migration into a scraped wound, which was reversed by L-NIL pretreatment. These results implicate enterocyte gap junctions as a target of the NO-mediated effects of macrophages during intestinal inflammation, particularly where enterocyte migration is impaired.

inflammation; intestinal restitution; enterocyte migration; necrotizing enterocolitis

This article has been cited by other articles:

				D. Ortiz-Masia, C. Hernandez, E. Quintana, M. Velazquez, S. Cebrian, A. Riano, S. Calatayud, J. V. Esplugues, and M. D. Barrachina iNOS-derived nitric oxide mediates the increase in TFF2 expression associated with gastric damage: role of HIF-1 FASEB J, January 1, 2010; 24(1): 136 - 145. [Abstract] [Full Text] [PDF]