Interleukin-12 treatment restores normal resistance to bacterial challenge after burn injury.
BACKGROUND
Preliminary studies in this laboratory have shown that treatment with interleukin-12 (IL-12), a cytokine that induces expression of the T-helper-1 lymphocyte phenotype, in an animal model of burn injury increased survival after a septic challenge. The purpose of this study was to define the efficacy of IL-12 therapy and to explore its mechanism of action.


METHODS
Adult male A/J mice were subjected to 25% full-thickness scald or sham burn. Starting on day 3 after burn, groups of mice received five daily injections of IL-12, interferon-gamma (IFN-gamma), or saline solution. Some animals received anti-IFN-gamma monoclonal antibody. At day 10 most animals underwent cecal ligation and puncture (CLP) and were observed for survival. Some animals were killed at day 10, and CD4-enriched splenocytes were stimulated with anti-CD3 antibody or concanavalin A and were studied for cytokine production and mRNA expression.


RESULTS
IL-12 treatment, 25 ng daily for 5 days, increased survival of the burn group after CLP to that of the sham burn control group. Anti-IFN-gamma antibody, 500 micrograms, administered 1 day before IL-12 treatment, reduced the efficacy of IL-12. IFN-gamma treatment, 7000 units, moderately increased survival. IL-12 had no effect on survival of the sham burn group. At the time of CLP IL-12 therapy had induced a marked decrease in CD4+ lymphocyte IL-4 and a moderate increase in IFN-gamma production and mRNA expression without affecting IL-2.


CONCLUSIONS
IL-12 is the most effective therapy so far tested in this burn plus CLP model. It acts at least in part through IFN-gamma. However, IFN-gamma therapy was not as effective as IL-12.
O'Suilleabhain
C
C
Department of Surgery, Harvard Medical School/Brigham and Women's Hospital, Boston, Mass. 02115, USA.
O'Sullivan
S T
ST
Kelly
J L
JL
Lederer
J
J
Mannick
J A
JA
Rodrick
M L
ML
D000818:Animals; D001419:Bacteria / Q000276:immunology; D002056:Burns / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000235:genetics; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D016019:Survival Analysis
D016207:Cytokines; D012333:RNA, Messenger; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma