Interleukin-10 mediates the protective effect of Linomide by reducing CXC chemokine production in endotoxin-induced liver injury.
The immunomodulator Linomide has been shown to protect against septic liver injury by reducing hepatic accumulation of leukocytes although the detailed anti-inflammatory mechanisms remain elusive. This study examined the effect of Linomide on the production of CXC chemokines, including macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC) and interleukin-10 (IL-10) in lipopolysaccharide (LPS)/d-galactosamine (Gal)-induced liver injury in mice. It was found that pretreatment with 300 mg kg(-1) of Linomide markedly suppressed leukocyte recruitment, perfusion failure, and hepatocellular damage and apoptosis in the liver of endotoxemic mice. Administration of Linomide inhibited endotoxin-induced gene expression of MIP-2 and KC and significantly reduced the hepatic production of MIP-2 and KC by 63 and 80%, respectively. Moreover, it was found that Linomide increased the liver content of IL-10 by more than three-fold in endotoxemic mice. The protective effect of Linomide against endotoxin-induced inflammation and liver injury was abolished in IL-10-deficient mice, suggesting that the beneficial effect of Linomide is dependent on the function of IL-10. Taken together, these novel findings suggest that the protective effect of Linomide is mediated via local upregulation of IL-10, which in turn decreases the generation of CXC chemokines and pathological recruitment of leukocytes in the liver of endotoxemic mice.
Li
Xiang
X
Department of Surgery, Malmö University Hospital, Lund University, Sweden.
Klintman
Daniel
D
Sato
Tohru
T
Hedlund
Gunnar
G
Schramm
René
R
Jeppsson
Bengt
B
Thorlacius
Henrik
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000502:physiology*; D019410:Interleukin-16 / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D004731:Endotoxins; D006912:Hydroxyquinolines; D007155:Immunologic Factors; D036341:Intercellular Signaling Peptides and Proteins; D019410:Interleukin-16; D016753:Interleukin-10; C045282:roquinimex; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase