Essential role of neutrophil mobilization in concanavalin A-induced hepatitis is based on classic IL-6 signaling but not on IL-6 trans-signaling.
Neutrophil depleted mice are protected from concanavalin A-mediated hepatitis, showing that neutrophils are critical for cellular liver damage. Interleukin-6 has pro- and anti-inflammatory properties and mediates neutrophil recruitment in diseases such as rheumatoid arthritis. In classic signaling, interleukin-6 binds to the membrane-bound interleukin-6-receptor and initiates signaling via gp130. In interleukin-6 trans-signaling, the agonistic soluble interleukin-6-receptor can form a soluble interleukin-6/interleukin-6-receptor complex and stimulate cells which only express gp130 but no interleukin-6-receptor. Interleukin-6 trans-signaling was shown to be important for liver regeneration and development of liver adenomas. Here, we show that blocking classic interleukin-6 signaling but not interleukin-6 trans-signaling reduced concanavalin A-induced liver damage in mice, with reduced liver STAT3 phosphorylation and liver neutrophil accumulation. However, the level of neutrophil-attracting chemokine KC is only reduced by inhibition of interleukin-6 trans-signaling. Analysis of circulating neutrophils after concanavalin A challenge revealed that classic interleukin-6 signaling is required for the mobilization of blood neutrophils. Reduced neutrophil infiltration was accompanied by increased levels of hepatoprotective monocyte chemoattractant protein-1 and reduced level of hepatodestructive interleukin-4. Abrogated classic interleukin-6 signaling in concanavalin A-mediated hepatitis exhibited liver-protective effects indicating that interleukin-6 classic but not interleukin-6 trans-signaling is responsible for liver damage. Classic interleukin-6 signaling is required to mount an efficient neutrophilia during concanavalin A-induced immune response, which might have clinical implications in the regard that blocking global interleukin-6 signaling pathways is a treatment option in different chronic inflammatory diseases.
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Sven
S
Malchow
Wolfgang
W
Thaiss
Nathalie
N
Jänner
Georg H
GH
Waetzig
Jessica
J
Gewiese-Rabsch
Christoph
C
Garbers
Kosuke
K
Yamamoto
Stefan
S
Rose-John
Jürgen
J
Scheller
D000818:Animals; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism; D003208:Concanavalin A / Q000633:toxicity; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000633:toxicity; D020556:Neutrophil Infiltration / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D018932:Chemokine CCL2; D015850:Interleukin-6; D008934:Mitogens; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D003208:Concanavalin A; D050822:Cytokine Receptor gp130