Electric foot-shock stress drives TNF-alpha production in the liver of IL-6-deficient mice.
OBJECTIVE
Accumulating evidence has shown that interleukin-6 (IL-6) has pleiotropic effects on a variety of biological functions, including its antiapoptotic potential during liver injury. Our previous work demonstrated that restraint stress-induced elevation of plasma IL-6 negatively regulates plasma tumor necrosis factor-alpha (TNF-alpha). Herein, we further clarified the mechanism underlying the above finding and investigated the effect of IL-6 on liver apoptosis triggered by stress.


METHODS
Male C57BL/6J and IL-6-deficient C57BL/SV129 mice were exposed to 1 h of electric foot-shock stress. Thereafter, the serum, liver and spleen TNF-alpha levels were measured at several time points. Serum alanine aminotransferase (ALT), liver caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) activities were analyzed to evaluate the severity of liver injury and apoptosis.


RESULTS
The liver, but not the spleen, of the IL-6-deficient mice exhibited a significant increase in TNF-alpha level after stress in parallel with serum TNF-alpha elevation, whereas no such TNF-alpha responses were found in the wild animals. No significant differences in stress-induced elevation of serum ALT levels, liver caspase-3 activities and the number of TUNEL-positive hepatocytes were found between the wild and IL-6-deficient mice.


CONCLUSIONS
Taken together, these results indicate that IL-6 may play a critical role in suppressing TNF-alpha production in the liver, thereby decreasing the blood TNF-alpha level. In contrast, IL-6 secretion was shown to have no protective effect on stress-triggered liver injury.
Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. chidayo@cephal.med.kyushu-u.ac.jp
Yoichi
Y
Chida
Nobuyuki
N
Sudo
Yoshitomo
Y
Motomura
Chiharu
C
Kubo
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004597:Electroshock / Q000009:adverse effects; D005528:Foot / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics*; D008099:Liver / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008107:Liver Diseases / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015213:Neuroimmunomodulation / Q000276:immunology; D013312:Stress, Physiological / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases