Interleukin-10 mediates the protective effect of Linomide by reducing CXC chemokine production in endotoxin-induced liver injury

1 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. 2 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. 3 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. 4 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. 5 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. (Less)