IL-1 cytokine family members and NAFLD: Neglected in metabolic liver inflammation

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver disease throughout the world [1]. It is currently considered as the hepatic manifestation of metabolic syndrome and reflects a large spectrum of liver diseases ranging from rather benign steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma [2,3]. The pathogenesis of NAFLD involves various hits including lipotoxicity, gut-derived signals such as endotoxin, signals from the innate immune system such as toll like receptors (TLRs) or pro-inflammatory cytokines, oxidative stress, and others. There is increasing evidence that mediators released from the adipose tissue of obese subjects, such as adipocytokines and classical cytokines, are key players in NAFLD [4]. NAFLD is frequently associated with morbid obesity which is often accompanied by chronic inflammation. Obesity and associated insulin resistance are characterized by increased adipose tissue expression of various pro-inflammatory mediators such as tumour necrosis factor-alpha (TNFa), interleukin-1 alpha/beta (IL-1ab), IL-6, and others [5]. Several IL-1 family (IL-1F) cytokine members are produced by human adipose tissue in case of obesity. Whereas certain IL-1F members such as IL-1a, IL-1b, or IL-18 are potently pro-inflammatory, others such as IL-1 receptor antagonist (IL-1Ra) or IL-37 (previously named IL-1F7) are antiinflammatory [6,7]. Processing of IL-1b or IL-18 requires cleavage by caspase-1, a protease under the control of the inflammasome [8]. Caspase-1 and IL-1b activity in adipose tissue is increased in both diet-induced and genetically induced animal models of obesity and mice deficient in caspase-1 or obese animals treated with a caspase-1 inhibitor are more insulin sensitive [9] .W e recently observed that IL-1b and IL-37 expression was much higher in subcutaneous/visceral adipose tissue compared to the liver suggesting that the adipose tissue might reflect a major source of inflammatory mediators in morbid obesity [10]. Systemic levels of IL-1Ra are increased in subjects with severe obesity although may not be able to sufficiently neutralize the activity