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them” to the best advantage for the present. “
“Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest 2012;122:3476-3489. (Reprinted with permission.) Alcoholic liver disease (ALD) is characterized by steatosis and upregulation of proinflammatory cytokines, including IL-1β. IL-1β, type I IL-1 receptor (IL-1R1), and IL-1 receptor antagonist (IL-1Ra) are all important regulators of the IL-1 signaling complex, which plays a role in inflammation. Furthermore, IL-1β maturation is dependent on caspase-1 (Casp-1). Using IL-1Ra-treated mice as well as 3 mouse models deficient in regulators of IL-1β activation (Casp-1 and ASC) or signaling

(IL-1R1), we found Daporinad supplier that IL-1β signaling is required for the development of alcohol-induced liver steatosis, inflammation, and injury. Increased IL-1β was due to upregulation of Casp-1 activity and inflammasome activation. The pathogenic role of IL-1 signaling in ALD was attributable to the activation of the inflammasome in BM-derived Kupffer cells. Importantly, in vivo intervention with a recombinant IL-1Ra blocked IL-1 signaling and markedly attenuated alcohol-induced liver inflammation, steatosis, and damage. Furthermore, physiological doses of IL-1β induced steatosis, increased the inflammatory and prosteatotic

chemokine MCP-1 in hepatocytes, and augmented TLR4-dependent upregulation of inflammatory signaling in macrophages. In conclusion, we demonstrated that Hydroxychloroquine cell line Casp-1-dependent upregulation of IL-1β and signaling mediated by IL-1R1 are crucial in ALD pathogenesis. Our findings suggest a potential role of IL-1R1 inhibition in the treatment of ALD. Alcoholic liver disease (ALD), which affects over 140 million people worldwide, continues to be a major health concern. Acute alcohol consumption induces fatty liver and prolonged ingestion new of alcohol causes progression to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma.1 The early stages of ALD are reversible with cessation from alcohol but the later stages of ALD such as cirrhosis or severe alcoholic hepatitis may not be reversible, often leading to mortality due to liver failure. There are no US Food and Drug Administration (FDA)-approved therapies for treating the later stages of ALD.2 Liver transplantation is the only option for prolonging life. Many factors have been identified that contribute to disease progression including drinking pattern, sex, nutrition, and obesity; however, despite years of extensive research, the underlying molecular mechanisms leading to disease progression are only partially understood.1 Altered immunity and inflammation are two components that have been identified as major contributors in the progression of ALD.