Role of IL-6 trans-signaling in CCl₄induced liver damage.
Interleukin-6 (IL-6) plays an important role in liver regeneration and protection against liver damage. In addition to IL-6 classic signaling via membrane bound receptor (mIL-6R), IL-6 signaling can also be mediated by soluble IL-6R (sIL-6R) thereby activating cells that do not express membrane bound IL-6R. This process has been named trans-signaling. IL-6 trans-signaling has been demonstrated to operate during liver regeneration. We have developed methods to specifically block or mimic IL-6 trans-signaling. A soluble gp130 protein (sgp130Fc) exclusively inhibits IL-6 trans-signaling whereas an IL-6/sIL-6R fusion protein (Hyper-IL-6) mimics IL-6 trans-signaling. Using these tools we investigate the role of IL-6 trans-signaling in CCl₄ induced liver damage. Blockade of IL-6 trans-signaling during CCl₄ induced liver damage led to higher liver damage, although induction of Cyp4502E1 and thus bioactivation of CCl₄ was unchanged. Depletion of neutrophils resulted in reduced liver transaminase levels irrespective of IL-6 trans-signaling blockade. Furthermore, IL-6 trans-signaling was important for refilling of hepatocyte glycogen stores, which were depleted 24 h after CCl₄ treatment. We conclude that IL-6 trans-signaling via the soluble IL-6R is important for the physiologic response of the liver to CCl₄ induced chemical damage.
Gewiese-Rabsch
Jessica
J
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Drucker
Claudia
C
Malchow
Sven
S
Scheller
Jürgen
J
Rose-John
Stefan
S
D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006003:Glycogen / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000502:physiology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000097:blood / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D015854:Up-Regulation
D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D017392:Thiobarbituric Acid Reactive Substances; D050822:Cytokine Receptor gp130; D006003:Glycogen; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; C519852:olamkicept