Role of interleukin-6 in a non-septic shock model induced by zymosan

In the present study, we used IL-6 knock-out mice (IL-6KO) to evaluate a po ssible role of IL-6 in the pathogenesis of non-septic shock induced by peri toneal injection of zymosan, A severe inflammatory response characterized b y peritoneal exudation, high peritoneal levels of nitrate/nitrite, and leuk ocyte infiltration into peritoneal exudate was induced by zymosan administr ation in wild-type control (WT) mice. This inflammatory process coincided w ith the damage to the lung and small intestine, as assessed by histological examination, Lung, small intestine and liver myeloperoxidase (MPO) activit y, indicative of neutrophil infiltration and lipid peroxidation, were signi ficantly increased in zymosan-treated WT mice, Peritoneal administration of zymosan in the WT mice also induced a significant increase in the plasma l evels of nitrite/nitrate and in the levels of peroxynitrite, 18 hours after zymosan challenge. Immunohistochemical examination demonstrated a marked i ncrease in the immunoreactivity to nitrotyrosine in the lung of zymosan-tre ated WT mice. Zymosan-treated IL-6KO showed significantly decreased mortali ty and inhibition of the development of peritonitis. In addition, IL-6KO mi ce showed significant protection from the development of organ failure, sin ce tissue injury and MPO was reduced in the lung, small intestine and liver . Furthermore, a significant reduction of suppression of mitochondrial resp iration, DNA strand breakage and reduction of cellular levels of NAD(+) was observed in ex vivo macrophages harvested from the peritoneal cavity of IL -6KO mice subjected to zymosan-induced non-septic shock. In vivo treatment with anti-IL-6 (5,000 ng/day per mouse, 24 and 1 hour before zymosan admini stration) significantly reduced the inflammatory process. Taken together, t he present study clearly demonstrates that IL-6 exerts a role in zymosan-in duced non-septic shock.