Does Stress-Induced Release of Interleukin-1 Cause Liver Injury?
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It is well established that repeated immobilization stress (RIS) is induced by increased levels of cytokines and the emergence of lesions in the liver. Our data prove that interleukin-1 (IL-1) causes liver lesions in stressed Wistar rats. In essence, the relationship between IL-1 and stress-induced liver injury is based on three findings: (1) IL-1β treatment causes liver inflammation, consisting of infiltrating monocytes and the appearance of necrosis by increasing lipid peroxidation and protein carbonylation. Positive correlations between the content of heptane-soluble diene conjugates and an area of necrosis, as well as between content carbonylated proteins and an area of necrosis, were found after injection of IL-1β to unstressed rats. (2) RIS is accompanied by increased levels of circulating IL-1β and corticosterone. In the liver, stress causes the emergence of foci of necrosis with perivascular and lobular infiltration of mononuclear cells as well as increased free radical oxidation. Moreover, there were observed down-regulations of cytochrome P450 (CYP)-dependent enzymes, CYP1A1 activities, and decreased CYP1A1 mRNA content. Positive correlations between the level of circulating IL-1β and necrosis areas, as well as between circulating IL-1β and the content of heptane-soluble diene conjugates, were observed in stressed rats. In addition, the positive correlation between necrosis foci and heptane-soluble diene conjugates was revealed after stress cessation. (3) Use of the IL-1 receptor antagonist Anakinra at a dose of 2 μg/kg to treat the effects of stress prevents infiltration of mononuclear cells and reduces the level of free radical oxidation as well as necrosis of lesions. As a result, blocking IL-1 receptors with an antagonist significantly rescues stress-induced liver injury, suggesting that IL-1 might be involve in the cascade of liver injury that initiated by sustained stress.
KeywordsInterleukin-1 Stress Lipid peroxidation Carbonylated proteins
Ethoxyresorufin O-deethylase activity
Interleukin-1 receptor antagonist
Repeated immobilization stress
- KD + CT
Ketodienes and conjugated trienes
Reactive antigen species
Serum separation tube
The authors acknowledge Professor Ilya Volchegorskii for helpful insights on the data and an earlier version of the manuscript. This research was supported by the Russian Foundation for Basic Research. Grants 10-04-96091 r_ural_and 11-04-01378-a, GK No. 2012055-Г316.
Conflict of interest
No authors have a conflict of interest with regards to the research being reported in this manuscript.
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