Staphylococcal Enterotoxin A-Induced Hepatotoxicity Is Predominately Mediated by Fas Ligand (CD95L)

Objective:To determine the role of tumor necrosis factor α (TNF-α) and Fas ligand (FasL, CD95L) in superantigen-induced and endotoxin-induced liver injury. Summary Background Data:Gram-positive bacteria are increasingly common causes of sepsis and multiorgan failure, but the pathophysiologic mechanisms of superantigen-provoked hepatotoxicity remain elusive. Methods:Intravital fluorescence microscopy was used to study the liver microcirculation in mice challenged with superantigen (staphylococcal enterotoxin A, SEA) or endotoxin (lipopolysaccharide, LPS) combined with d-galactosamine. Results:Administration of 10 &mgr;g LPS and 50 &mgr;g SEA caused similar hepatocellular damage as determined by liver enzymes and apoptosis. Notably, TNF-α–deficient mice were completely protected against hepatic injury provoked by LPS, whereas no protection was observed in response to SEA. On the other hand, FasL-deficient mice were protected against liver injury induced by SEA, but no protection was found when challenged with LPS. LPS increased clear-cut leukocyte recruitment, whereas SEA had no significant effect on leukocyte responses in the liver microcirculation. Leukocyte responses to LPS were decreased by >56% in TNF-α gene-targeted animals. Moreover, antiadhesive therapy, ie, immunoneutralization of P-selectin, which is an effective inhibitor of leukocyte recruitment, protected against LPS-induced but not against SEA-induced hepatic damage. Conclusions:These novel findings demonstrate that the mechanisms of hepatic injury in endotoxin-induced and superantigen-induced sepsis are principally different. On one hand, SEA-provoked hepatotoxicity is mediated by FasL and is not associated with leukocyte recruitment. On the other hand, liver damage provoked by LPS is mediated by TNF-α and characterized by prominent leukocyte responses. These data may facilitate development of more specific therapies against sepsis of different origins.

[1]  B. Jeppsson,et al.  Critical role of CXC chemokines in endotoxemic liver injury in mice , 2004, Journal of leukocyte biology.

[2]  H. Thorlacius,et al.  Important Role of P-Selectin for Leukocyte Recruitment, Hepatocellular Injury, and Apoptosis in Endotoxemic Mice , 2004, Clinical Diagnostic Laboratory Immunology.

[3]  D. Mannino,et al.  The epidemiology of sepsis in the United States from 1979 through 2000. , 2003, The New England journal of medicine.

[4]  A. Tarkowski,et al.  Microbial Superantigens as Virulence Factors and Ways to Counteract Their Actions , 2003, Scandinavian journal of infectious diseases.

[5]  H. Rüdiger,et al.  Tumor necrosis factor alpha, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver. , 2002, Gastroenterology.

[6]  M. Menger,et al.  Leukocyte recruitment in hepatic injury: selectin-mediated leukocyte rolling is a prerequisite for CD18-dependent firm adhesion. , 2002, Journal of hepatology.

[7]  S. Foster,et al.  Peptidoglycan and Lipoteichoic Acid from Staphylococcus aureus Induce Tumor Necrosis Factor Alpha, Interleukin 6 (IL-6), and IL-10 Production in Both T Cells and Monocytes in a Human Whole Blood Model , 2000, Infection and Immunity.

[8]  L. Moldawer,et al.  Lipopolysaccharide and D-galactosamine-induced hepatic injury is mediated by TNF-alpha and not by Fas ligand. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[9]  P. Kubes,et al.  Molecular mechanisms of tumor necrosis factor α–stimulated leukocyte recruitment into the murine hepatic circulation , 2000, Hepatology.

[10]  S. Opal,et al.  Clinical gram-positive sepsis: does it fundamentally differ from gram-negative bacterial sepsis? , 1999, Critical care medicine.

[11]  R. Gaynes,et al.  Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System. , 1999, Critical care medicine.

[12]  H. Mannherz,et al.  Cold‐induced apoptosis in cultured hepatocytes and liver endothelial cells: mediation by reactive oxygen species , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[13]  D. Howell,et al.  L-selectin and ICAM-1 mediate reperfusion injury and neutrophil adhesion in the warm ischemic mouse liver. , 1998, American journal of physiology. Gastrointestinal and liver physiology.

[14]  D. Wallach,et al.  Death-inducing functions of ligands of the tumor necrosis factor family: a Sanhedrin verdict. , 1998, Current Opinion in Immunology.

[15]  C. J. Dunn,et al.  Neutrophil margination and extravasation in sinusoids and venules of liver during endotoxin-induced injury. , 1997, The American journal of physiology.

[16]  J. Carlet,et al.  INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. , 1996, Critical care medicine.

[17]  J. Vincent,et al.  The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. , 1995, JAMA.

[18]  J. Cavaillon,et al.  Comparative study of cytokine release by human peripheral blood mononuclear cells stimulated with Streptococcus pyogenes superantigenic erythrogenic toxins, heat-killed streptococci, and lipopolysaccharide , 1994, Infection and immunity.

[19]  J. Vincent,et al.  Influence of an anti‐tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis , 1993, Critical care medicine.

[20]  U. Andersson,et al.  Endotoxin and Staphylococcus aureus enterotoxin A induce different patterns of cytokines. , 1992, Cytokine.

[21]  C. Smith,et al.  Neutrophil-induced liver cell injury in endotoxin shock is a CD11b/CD18-dependent mechanism. , 1991, The American journal of physiology.

[22]  P. Marrack,et al.  The staphylococcal enterotoxins and their relatives. , 1990, Science.

[23]  J. Holman,et al.  Hepatocyte Injury During Post‐Operative Sepsis: Activated Neutrophils as Potential Mediators , 1988, Journal of leukocyte biology.

[24]  P. Schlievert.  Enhancement of host susceptibility to lethal endotoxin shock by staphylococcal pyrogenic exotoxin type C , 1982, Infection and immunity.