PARADOXICAL SYNERGISTIC EFFECTS OF TUMOUR NECROSIS FACTOR AND INTERLEUKIN 1 IN MURINE GUT-DERIVED SEPSIS WITH PSEUDOMONAS AERUGINOSA

Abstract

The authors evaluated the synergistic effect of tumour necrosis factor (TNF) and interleukin 1 (IL-1) in gut-derived sepsis in mice. After colonization of Pseudomonas aeruginosa strain D4 in the gastrointestinal tract, cyclophosphamide was administered to induce bacterial translocation of the P. aeruginosa and thereby to cause gut-derived sepsis. In this model, treatment either with 8μg/kg of recombinant human TNF-α (rhTNF-α) or 2μg/kg of recombinant human interleukin 1α (rhIL-1α) solely did not affect the mortality, whereas combined administration of the same doses of rhTNF-α and rhIL-1α significantly increased the mortality rate in comparison with saline-treated mice. Bacterial counts in liver and blood were significantly higher in rhTNF-α and rhIL-1α treated mice than in saline-treated mice. Endogenous TNF-α and IL-1β productions were stimulated after combined treatment with rhTNF-α and rhIL-1αOn the contrary to these adverse effects, combined treatment with 500μg/kg of rhTNF-α and 50μg/kg of rhIL-1α on the day before the administration of cyclophosphamide significantly reduced the mortality from septic infection. We conclude that TNF and IL-1 synergistically affect the mortality of mice after gut-derived sepsis due to P. aeruginosa in mice and the timing of treatment with these cytokines causes both extremes in their effects.