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.