Therapeutic potential of interleukin 1 inhibitors in the treatment of alcoholic liver disease

Abstract

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-1Ratreated mice as well as 3 mouse models deficient in regulators of IL-1β activation (Casp-1 and ASC) or signaling (IL-1R1), we found 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 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.

Fig. 1

A model depicting the roles of inflammasome-IL-1 in alcoholic liver injury. Chronic alcohol consumption increases gut permeability and subsequently results in elevation of LPS in the portal blood, which enhances Toll-like receptor 4 (TLR4)-mediated TNF-α production and hepatic cytotoxicity. Chronic alcohol consumption also upregulates the inflammasome and casp-1 in KCs, leading to increased IL-1β and enhanced IL-1 signaling. IL-1β not only directly induces hepatic steatosis and injury but also enhances LPS-mediated TNF-α production, which further exacerbates liver injury. IL-1 inhibitors may have therapeutic potential for the treatment of ALD by blocking IL-1 signaling in the liver. Arrow lines indicate stimulation; Dot arrow lines indicate exacerbation; Arrow lines with two double lines indicate inhibition.