TY - JOUR
T1 - The resistance of P. acnes-primed interferon γ-deficient mice to low-dose lipopolysaccharide-induced acute liver injury
AU - Shimizu, Yoshiaki
AU - Margenthaler, Julie A.
AU - Landeros, Keith
AU - Otomo, Naoki
AU - Doherty, Gerard
AU - Flye, M. Wayne
N1 - Funding Information:
Abbreviations: LPS, lipopolysaccharide; IL, interleukin; IFN, interferon; NK, natural killer cells; B6, C57BL/6; GKO, IFN-γ deficient; TNF, tumor necrosis factor; Ab, antibody; RT-PCR, reverse transcriptase-polymerase chain reaction; mRNA, messenger RNA. From the Department of Surgery, Washington University School of Medicine, St. Louis, MO. Received August, 2001; accepted January 15, 2002. Supported by National Institutes of Health grant DK 52232. Address reprint requests to: M. Wayne Flye, M.D., Ph.D., Department of Surgery, Washington University School of Medicine, One Barnes-Jewish Hospital Pl., Ste. 5103, St. Louis, MO 63110. E-mail: [email protected]; fax: 314-454-3923. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3504-0010$35.00/0 doi:10.1053/jhep.2002.32484
PY - 2002
Y1 - 2002
N2 - Endotoxin has been identified as a principal mediator of sepsis, often with resulting multiple organ failure. Although interferon γ (IFN-γ) has a central role in controlling bacterial infection through the activation of macrophages and T lymphocytes, it can also enhance the harmful effects of the inflammatory response. To examine the role of IFN-γ in lipopolysaccharide (LPS)-induced injury, we administered LPS (20 or 800 μg/mouse) alone or as low-dose LPS (20 μ/mouse) 7 days after heat-killed Propionibacterium acnes (P. acnes) injection into wild-type C57BL/6 (B6) mice or IFN-γ-deficient (GKO) mice (B6 background). Although low-dose (20 μg) LPS alone had no effect on survival, the administration of 800 μg LPS alone resulted in 100% mortality in both B6 and GKO mice without significant hepatic mononuclear cellular infiltration or differences in elevated plasma tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and IL-12 levels. In contrast, mortality after low-dose (20 μg) LPS challenge in P. acnes-primed B6 mice was 100%, but 0% in GKO mice. In vivo plasma cytokine (IFN-γ, TNF-α, IL-6, and IL-12) levels and in vitro cytokine production by hepatic mononuclear cells were significantly higher in B6 mice compared with GKO mice. Associated hepatic mononuclear cellular infiltration, multifocal liver necrosis, hepatomegaly, and splenomegaly were found in B6 mice, but not in GKO mice. Finally, the anti-inflammatory NK1.1+CD4+ cell proportion of hepatic infiltrating mononuclear cell numbers 7 days after P. acnes administration was significantly reduced in B6 compared with GKO mice, whereas the proportion of inflammatory NK1.1+CD4- cells was increased. In conclusion, these data suggest that IFN-γ mediates P. acnes-primed low-dose LPS injury through the hepatic infiltration of mononuclear cells and the subsequent elevation of inflammatory cytokines after LPS challenge, whereas the lethal effects of high-dose LPS alone does not depend on the presence of IFN-γ.
AB - Endotoxin has been identified as a principal mediator of sepsis, often with resulting multiple organ failure. Although interferon γ (IFN-γ) has a central role in controlling bacterial infection through the activation of macrophages and T lymphocytes, it can also enhance the harmful effects of the inflammatory response. To examine the role of IFN-γ in lipopolysaccharide (LPS)-induced injury, we administered LPS (20 or 800 μg/mouse) alone or as low-dose LPS (20 μ/mouse) 7 days after heat-killed Propionibacterium acnes (P. acnes) injection into wild-type C57BL/6 (B6) mice or IFN-γ-deficient (GKO) mice (B6 background). Although low-dose (20 μg) LPS alone had no effect on survival, the administration of 800 μg LPS alone resulted in 100% mortality in both B6 and GKO mice without significant hepatic mononuclear cellular infiltration or differences in elevated plasma tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and IL-12 levels. In contrast, mortality after low-dose (20 μg) LPS challenge in P. acnes-primed B6 mice was 100%, but 0% in GKO mice. In vivo plasma cytokine (IFN-γ, TNF-α, IL-6, and IL-12) levels and in vitro cytokine production by hepatic mononuclear cells were significantly higher in B6 mice compared with GKO mice. Associated hepatic mononuclear cellular infiltration, multifocal liver necrosis, hepatomegaly, and splenomegaly were found in B6 mice, but not in GKO mice. Finally, the anti-inflammatory NK1.1+CD4+ cell proportion of hepatic infiltrating mononuclear cell numbers 7 days after P. acnes administration was significantly reduced in B6 compared with GKO mice, whereas the proportion of inflammatory NK1.1+CD4- cells was increased. In conclusion, these data suggest that IFN-γ mediates P. acnes-primed low-dose LPS injury through the hepatic infiltration of mononuclear cells and the subsequent elevation of inflammatory cytokines after LPS challenge, whereas the lethal effects of high-dose LPS alone does not depend on the presence of IFN-γ.
UR - http://www.scopus.com/inward/record.url?scp=0036207887&partnerID=8YFLogxK
U2 - 10.1053/jhep.2002.32484
DO - 10.1053/jhep.2002.32484
M3 - Article
C2 - 11915026
AN - SCOPUS:0036207887
SN - 0270-9139
VL - 35
SP - 805
EP - 814
JO - Hepatology
JF - Hepatology
IS - 4
ER -