Acute induction of human IL-8 production by intestinal epithelium triggers neutrophil infiltration without mucosal injury.
OBJECTIVE
Neutrophil migration in the intestine depends on chemotaxis of neutrophils to CXC chemokines produced by epithelial cells. The goal of this project was to determine if acute induction of a CXC chemokine gradient originating from intestinal epithelial cells is sufficient to induce neutrophil influx into intact intestinal tissue.


RESULTS
The authors developed a double transgenic mouse model with doxycycline induced human IL-8 expression restricted to intestinal epithelial cells. Doxycycline treatment of double transgenic mice for three days resulted in a 50-fold increase in the caecal IL-8 concentration and influx of neutrophils into the lamina propria. Although neutrophils entered the paracellular space between epithelial cells, complete transepithelial migration was not observed. Doxycycline treatment also increased the water content of the caecal and colonic stool, indicating dysfunctional water transport. However, the transmural electrical resistance was not decreased. Neutrophils recruited to the intestinal epithelium did not show evidence of degranulation and the epithelium remained intact as judged by histology.


CONCLUSIONS
This conditional transgenic model of chemokine expression provides evidence that acute induction of IL-8 in the intestinal epithelium is sufficient to trigger neutrophil recruitment to the lamina propria, but additional activation signals are needed for full activation and degranulation of neutrophils, mucosal injury, and complete transepithelial migration.
Department of Pathology, Emory University, 105D Whitehead Building, 615 Michael Street, Atlanta, GA 30322, USA.
T
T
Kucharzik
J T
JT
Hudson
A
A
Lügering
J A
JA
Abbas
M
M
Bettini
J G
JG
Lake
M E
ME
Evans
T R
TR
Ziegler
D
D
Merlin
J L
JL
Madara
I R
IR
Williams
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001834:Body Water / Q000378:metabolism; D002432:Cecum / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003106:Colon / Q000276:immunology; D004318:Doxycycline / Q000494:pharmacology; D005243:Feces / Q000737:chemistry; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects / Q000276:immunology; D016209:Interleukin-8 / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000648:ultrastructure; D013752:Tetracycline / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D016209:Interleukin-8; D013752:Tetracycline; D004318:Doxycycline