| Research Abstract |
Cytokines and chemical mediators produced by endotoxin are thought to be the cause of endotoxin shock. Recently we investigated plasma cytokine and endotoxin levels in septic shock patients, and have found two types of septic shock, e.g, endotoxin + TNF-alpha + IL-2 type and IL-1beta and IL-6 type. In the former type of shock, two cytokines with extremely high levels were already present several days before the onset and shock was associated with sudden endotoxemia. However, only endotoxemia without previous elevation of cytokine levels did not induce shock. These are different from the previous concept as mentioned above, and the roles of these cytokines as to enhancement of endotoxin sensitivity were suggested. The purpose of this study is to confirm the roles of TNF-alpha and IL-2 for the induction of lethality by sublethal dose of endotoxin.
Results were as follows : 1) Sub-lethal dose of endotoxin and recombinant human (rh)TNF-alpha were synergistically induced lethality and hypote
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nsion in mice. 2) Recombinant human (rh)IL-2 alone did not show lethality in mice but shortened the interval from the injection to death by endotoxin and rhTNF-alpha. 3) The lethality induced by endotoxin, rhTNF-alpha and IL-2 was inhibited by polymyxin B injected 30 min before or soon after the mixture. 4) The lethality induced by high dose of endotoxin alone was inhibited by PAF antagonist or protease inhibitor, but the lethality by endotoxin. rhTNF-alpha and IL-2 was not. 5) IL-2 did not induce hypotension and had no effect on hypotension by endotoxin and rhTNF-alpha during early 180 min after the injection (we did not observed later changes). 6) Recombinant mouse (rm)TNF-alpha also had synergistic effect with endotoxin in lethality and hypotension. 7) Endotoxin induced the production of nitric oxide(NO) which accounts for the biological properties of endothelium-derived relaxing factor (EDRF) ; hypotension inducer. 8) rmTNF-alpha,but not rhTNF-alpha synergistically enhanced the NO production by endotoxin. 9) IL-2 in higher doses synergistically enhanced the NO production by endotoxin.
These results indicate that endotoxin and TNF-alpha induce hypotension and lethality. as previously reported by other authors, and IL-2 synergistically enhanced the lethality by endotoxin and TNF-alpha. However, IL-2 did not enhanced the hypotension in early period induced by endotoxin and TNF-alpha.
Thus, these results suggest that IL-2 involves in the pathogenesis of endotoxin shock in human. Less
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