Anti-tumor necrosis factor-alpha therapy during murine Klebsiella pneumoniae bacteremia: increased mortality in the absence of liver injury

Shock. 2003 Oct;20(4):309-15. doi: 10.1097/01.shk.0000087203.34916.45.


Klebsiella pneumoniae is a leading cause of gram-negative bacterial pneumonia, often resulting in bacteremia concurrent with the localized pulmonary infection. The beneficial role of tumor necrosis factor (TNF)-alpha during pulmonary infection has been well documented; however, consequences of TNF-alpha production during systemic bacterial infection are controversial. A murine model of K. pneumoniae was developed to address this important issue. Liver-associated TNF-alpha mRNA was induced within 30 min after intravenous bacterial inoculation and remained elevated through 6 h before returning to near-baseline at 24 h postinfection. Intravenous K. pneumoniae infection induced liver cellular injury that was completely ablated when mice were pretreated with a neutralizing anti-TNF-alpha antibody. Interestingly, this reduction in liver injury failed to translate into improved survival. Mice receiving anti-TNF-alpha continued to succumb to the infection even out to day 10 postinfection. Bacterial clearance after TNF-alpha neutralization was significantly impaired at later time points during infection. Correlating with impaired bacterial clearance was diminished production of liver-associated MIP-2, MIP-1alpha, MCP-1, and interferon-gamma. Further evidence of diminished antibacterial immune responses was noted when the activational status of splenic natural killer cells in anti-TNF-alpha-treated mice was examined 24 h postinfection. Natural killer cells displayed decreased CD69 expression. Combined, these data indicate that the beneficial effects of TNF-alpha during systemic K. pneumoniae infection outweigh the detrimental effects of TNF-alpha-mediated hepatocyte cellular injury. Anti-TNF-alpha therapy, although preventing liver injury during blood-borne bacterial infection, results in a dampened anti-bacterial host response, resulting in decreased bacterial clearance and overall survival.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Bacteremia / immunology
  • Bacteremia / therapy*
  • Cytokines / biosynthesis
  • Gene Expression
  • Killer Cells, Natural / immunology
  • Klebsiella Infections / immunology
  • Klebsiella Infections / microbiology
  • Klebsiella Infections / therapy*
  • Klebsiella pneumoniae* / isolation & purification
  • Liver / immunology
  • Liver / injuries
  • Mice
  • Mice, Inbred C57BL
  • Neutralization Tests
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / genetics


  • Antibodies, Monoclonal
  • Cytokines
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha