Nuclear factor-kappa B activation promotes restitution of wounded intestinal epithelial monolayers.
Epithelial restitution, the movement of wound-edge cells into an area of epithelial cell denudation, is an important early step in the ulcer healing process. Growth factors regulate epithelial restitution, yet little is known about the transcriptional pathways that mediate their effects on cell migration. The transcription factor nuclear factor (NF)-kappaB is a master regulator of the host inflammatory response that is activated in the epithelium in intestinal inflammation, which often accompanies epithelial injury. We hypothesized that NF-kappaB may be an important transcriptional regulator of epithelial restitution. In an in vitro model of scrape-wounded monolayers of nontransformed rat intestinal epithelial (RIE-1) cells, NF-kappaB was activated in epithelial cells at the wound edge. Blocking of NF-kappaB activation by either pharmacological or genetic approaches inhibited intestinal epithelial restitution. Moreover, scrape wounding activated the epidermal growth factor receptor (EGFR) in cells at the wound edge, and, importantly, inhibiting EGFR tyrosine kinase activity decreased scrape wound-induced NF-kappaB activation and cell migration. These results indicate a novel role of NF-kappaB activation in a signaling pathway important for restitution and healing of intestinal epithelia. To the extent NF-kappaB may have parallel functions in vivo, they also suggest a need for caution in the proposed use of NF-kappaB inhibitors for the treatment of conditions associated with inflammation and injury of intestinal and other mucosal surfaces.
Egan
Laurence J
LJ
Laboratory of Mucosal Immunology, Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0623, USA.
de Lecea
Ana
A
Lehrman
Evan D
ED
Myhre
Gennett M
GM
Eckmann
Lars
L
Kagnoff
Martin F
MF
D000818:Animals; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology*; D051381:Rats
D016328:NF-kappa B; D066246:ErbB Receptors