A novel role for IL-18 in corticosterone-mediated intestinal damage in a two-hit rodent model of alcohol intoxication and injury.
Recent findings from our laboratory have shown that acute alcohol (EtOH) intoxication before burn injury impairs intestinal immunity and barrier functions. To further delineate the mechanism of impaired intestinal barrier function, the present study examined the role of corticosterone (CORT) and interleukin (IL)-18, as CORT and IL-18 are elevated following a combined insult of EtOH intoxication and burn injury. Male rats (approximately 250 g) were gavaged with EtOH to achieve a blood EtOH level of approximately 100 mg/dL prior to burn or sham injury (25% total body surface area). Immediately after injury, a group of rats was treated with CORT synthesis inhibitor metyrapone (25 mg/kg), with or without recombinant (r)IL-18 (50 microg/kg). Another group of rats was treated with caspase-1 inhibitor Ac-YVAD-CHO to block IL-18 production. On Day 1 after injury, there was a significant increase in blood CORT levels, intestinal levels of IL-18, neutrophil chemokines [cytokine-induced neutrophil chemoattractant 1 (CINC-1) and CINC-3], intercellular adhesion molecule-1, myeloperoxidase activity, and intestinal permeability in rats receiving a combined insult of EtOH and burn injury. Treatment of rats with CORT inhibitor or with caspase-1 inhibitor prevented the increase in all of the above parameters following a combined insult of EtOH and burn injury. Moreover, coadministration of rIL-18 in metyrapone-treated rats restored the above parameters, similar to those observed in rats receiving EtOH and burn injury. These findings suggest that a combined insult of EtOH and burn injury results in increased CORT levels, which in turn up-regulates intestinal IL-18 levels and thereby causes altered intestinal barrier function following a combined insult of EtOH intoxication and burn injury.
Li
Xiaoling
X
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Rana
Shadab N
SN
Schwacha
Martin G
MG
Chaudry
Irshad H
IH
Choudhry
Mashkoor A
MA
D000435:Alcoholic Intoxication / Q000378:metabolism; D000818:Animals; D002056:Burns / Q000378:metabolism*; D020170:Caspase 1 / Q000494:pharmacology; D061945:Caspase Inhibitors; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000378:metabolism; D003345:Corticosterone / Q000502:physiology*; D003911:Dextrans / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000502:physiology; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D061945:Caspase Inhibitors; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; D003911:Dextrans; D020382:Interleukin-18; C015219:fluorescein isothiocyanate dextran; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D020170:Caspase 1; D016650:Fluorescein-5-isothiocyanate; D003345:Corticosterone; D008797:Metyrapone