IL-1 cytokine family members and NAFLD: Neglected in metabolic liver inflammation
Authors: Herbert Tilg, Alexander R. Moschen
Journal: Journal of Hepatology (2011)

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver disease throughout the world [[1]Satapathy S.K. Sanyal A.J. Novel treatment modalities for nonalcoholic steatohepatitis.Trends Endocrinol Metab. 2010; 21: 668-675Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. 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 [2Feldstein A.E. Novel insights into the pathophysiology of nonalcoholic fatty liver disease.Semin Liver Dis. 2010; 30: 391-401Crossref PubMed Scopus (93) Google Scholar, 3Brunt E.M. Non-alcoholic fatty liver disease: what's new under the microscope?.Gut. 2011; 60: 1152-1158Crossref PubMed Scopus (33) Google Scholar]. 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]Tilg H. Moschen A.R. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.Hepatology. 2010; 52: 1836-1846Crossref PubMed Scopus (1421) Google Scholar]. 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 (TNFα), interleukin-1 alpha/beta (IL-1αβ), IL-6, and others [[5]Donath M.Y. Shoelson S.E. Type 2 diabetes as an inflammatory disease.Nat Rev Immunol. 2011; 11: 98-107Crossref PubMed Scopus (2144) Google Scholar]. 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-1α, IL-1β, or IL-18 are potently pro-inflammatory, others such as IL-1 receptor antagonist (IL-1Ra) or IL-37 (previously named IL-1F7) are anti-inflammatory [6Dinarello C.A. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.Blood. 2011; 117: 3720-3732Crossref PubMed Scopus (1315) Google Scholar, 7Nold M.F. Nold-Petry C.A. Zepp J.A. Palmer B.E. Bufler P. Dinarello C.A. IL-37 is a fundamental inhibitor of innate immunity.Nat Immunol. 2010; 11: 1014-1022Crossref PubMed Scopus (579) Google Scholar]. Processing of IL-1β or IL-18 requires cleavage by caspase-1, a protease under the control of the inflammasome [[8]Schroder K. Zhou R. Tschopp J. The NLRP3 inflammasome: a sensor for metabolic danger?.Science. 2010; 327: 296-300Crossref PubMed Scopus (760) Google Scholar]. Caspase-1 and IL-1β 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]Stienstra R. Joosten L.A. Koenen T. van Tits B. van Diepen J.A. van den Berg S.A. et al.The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity.Cell Metab. 2010; 12: 593-605Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar]. We recently observed that IL-1β 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]Moschen A.R. Molnar C. Enrich B. Geiger S. Ebenbichler C.F. Tilg H. Adipose and liver expression of IL-1 family members in morbid obesity and effects of weight loss.Mol Med. 2011; PubMed Google Scholar]. Systemic levels of IL-1Ra are increased in subjects with severe obesity although may not be able to sufficiently neutralize the activity of pro-inflammatory IL-1F members [[11]Meier C.A. Bobbioni E. Gabay C. Assimacopoulos-Jeannet F. Golay A. Dayer J.M. IL-1 receptor antagonist serum levels are increased in human obesity: a possible link to the resistance to leptin?.J Clin Endocrinol Metab. 2002; 87: 1184-1188Crossref PubMed Scopus (191) Google Scholar]. IL-1F members have been demonstrated to affect insulin/glucose metabolism and regulate metabolic dysfunction. IL-1β is upregulated in the adipose tissue of obese insulin-resistant mice and adipocyte-derived IL-1β has been shown to control liver cell insulin sensitivity [12Lagathu C. Yvan-Charvet L. Bastard J.P. Maachi M. Quignard-Boulange A. Capeau J. et al.Long-term treatment with interleukin-1beta induces insulin resistance in murine and human adipocytes.Diabetologia. 2006; 49: 2162-2173Crossref PubMed Scopus (227) Google Scholar, 13Nov O. Kohl A. Lewis E.C. Bashan N. Dvir I. Ben Shlomo S. et al.Interleukin-1beta may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation.Endocrinology. 2010; 151: 4247-4256Crossref PubMed Scopus (80) Google Scholar]. IL-1α−/− mice have lower fasting glucose and insulin levels and improved insulin sensitivity [[5]Donath M.Y. Shoelson S.E. Type 2 diabetes as an inflammatory disease.Nat Rev Immunol. 2011; 11: 98-107Crossref PubMed Scopus (2144) Google Scholar]. IL-1β is able to reduce insulin receptor substrate-1 expression at a transcriptional level through ERK dependent and independent mechanisms [[14]Somm E. Cettour-Rose P. Asensio C. Charollais A. Klein M. Theander-Carrillo C. et al.Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents.Diabetologia. 2006; 49: 387-393Crossref PubMed Scopus (87) Google Scholar]. Treatment of type 2 diabetes patients with recombinant human IL-1Ra improves glycemic control, clearly highlighting the role of inflammation in type 2 diabetes and insulin resistance [[15]Larsen C.M. Faulenbach M. Vaag A. Volund A. Ehses J.A. Seifert B. et al.Interleukin-1-receptor antagonist in type 2 diabetes mellitus.N Engl J Med. 2007; 356: 1517-1526Crossref PubMed Scopus (1340) Google Scholar]. In a diet-induced obesity model, treatment with XOMA 052, a neutralizing anti-IL-1β antibody, improved insulin sensitivity and led to beta-cell sparing [[16]Owyang A.M. Maedler K. Gross L. Yin J. Esposito L. Shu L. et al.XOMA 052, an anti-IL-1{beta} monoclonal antibody, improves glucose control and {beta}-cell function in the diet-induced obesity mouse model.Endocrinology. 2010; 151: 2515-2527Crossref PubMed Scopus (79) Google Scholar]. Elevated IL-1β, IL-6, or IL-1Ra concentrations predict risk for type 2 diabetes in humans [17Spranger J. Kroke A. Mohlig M. Hoffmann K. Bergmann M.M. Ristow M. et al.Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.Diabetes. 2003; 52: 812-817Crossref PubMed Scopus (1092) Google Scholar, 18Carstensen M. Herder C. Kivimaki M. Jokela M. Roden M. Shipley M.J. et al.Accelerated increase in serum interleukin-1 receptor antagonist starts 6 years before diagnosis of type 2 diabetes: whitehall II prospective cohort study.Diabetes. 2010; 59: 1222-1227Crossref PubMed Scopus (99) Google Scholar]. Type I IL-1 receptor (IL-1RI) may mediate various aspects of metabolic inflammation as free fatty acids, which are abundantly available in obesity, together with TLR stimulation up-regulate and induce pro-inflammatory cytokines, and IL-1RI engagement results in amplification of inflammation [[19]Boni-Schnetzler M. Boller S. Debray S. Bouzakri K. Meier D.T. Prazak R. et al.Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I.Endocrinology. 2009; 150: 5218-5229Crossref PubMed Scopus (237) Google Scholar]. This is of interest, as disruption of this receptor exerted significant protection from diet-induced insulin resistance independent of obesity [[20]de Roos B. Rungapamestry V. Ross K. Rucklidge G. Reid M. Duncan G. et al.Attenuation of inflammation and cellular stress-related pathways maintains insulin sensitivity in obese type I interleukin-1 receptor knockout mice on a high-fat diet.Proteomics. 2009; 9: 3244-3256Crossref PubMed Scopus (39) Google Scholar]. Overall, all these data suggest that IL-1F members might critically control insulin resistance and metabolic inflammation in various obesity-associated disorders. Kamari and colleagues addressed in this issue of the Journal an important and long overdue topic, namely the role of IL-1α/β in steatosis and steatohepatitis [[21]Kamari Y. Shaish A. Vax E. Shemesh S. Kandel-Kfir M. Arbel Y. et al.Lack of interleukin-1alpha or interleukin-1beta inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.J Hepatol. 2011; 55: 1086-1094Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar]. In their study, they used a diet-induced model of steatosis and steatohepatitis and observed a considerable increase in the hepatic expression of both IL-1 cytokines. Interestingly, despite demonstrating less inflammation, IL-1α−/− mice demonstrated increased hepatic cholesterol deposition and higher plasma cholesterol levels suggesting that hepatic fat storage and inflammation are not necessarily parallel events and certain intra-hepatic lipids might exert even protective, anti-inflammatory functions [[4]Tilg H. Moschen A.R. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.Hepatology. 2010; 52: 1836-1846Crossref PubMed Scopus (1421) Google Scholar]. It also fits with the observation that in certain instances inflammation may precede steatosis and with the fact that liver steatosis in many instances is a rather benign condition without subsequent inflammation [[4]Tilg H. Moschen A.R. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.Hepatology. 2010; 52: 1836-1846Crossref PubMed Scopus (1421) Google Scholar]. Both IL-1α and IL-1β-deficient mice were almost entirely protected from inflammation after diet-induced steatosis, suggesting that these pro-inflammatory IL-1 cytokines might be crucially involved in the development of liver inflammation. Importantly, IL-1α and IL-1β KO mice demonstrated lower mRNA levels of both inflammation and fibrosis-related genes including a significant decrease in TGFβ, highlighting the close pathophysiological relationship between inflammation and fibrosis. A key insight of their studies was also the fact that hepatic and not bone-marrow-derived-IL-1α/β deficiency protected against diet-induced inflammation and fibrosis. The relevance of this data is, however, uncertain as it has been demonstrated that full reconstitution of Kupffer cells may occur beyond 9 weeks after bone marrow transplantation and the authors only allowed a 2 week recovery period after transplantation before starting the atherogenic diet. Experiments with hepatocyte- or Kupffer cell/macrophage-specific IL-1α/β− mice are needed to clearly address these issues. This is of importance as other extrahepatic cell types such as adipocytes could be important sources of IL-1α/β in obesity, as suggested by several studies [[10]Moschen A.R. Molnar C. Enrich B. Geiger S. Ebenbichler C.F. Tilg H. Adipose and liver expression of IL-1 family members in morbid obesity and effects of weight loss.Mol Med. 2011; PubMed Google Scholar]. The results presented in the Kumari study are in accordance with another recent report showing that, in a diet-induced model of obesity, TLR9 controls steatohepatitis via IL-1β [[22]Miura K. Kodama Y. Inokuchi S. Schnabl B. Aoyama T. Ohnishi H. et al.Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice.Gastroenterology. 2010; 139: 323-334Abstract Full Text Full Text PDF PubMed Scopus (504) Google Scholar]. These authors also found that IL-1β increases lipid accumulation in hepatocytes, regulates inflammation, hepatic insulin resistance, and fibrosis. Overall, these studies together convincingly show that IL-1α/β are important mediators in metabolic liver inflammation. In summary, this work by Kumari and colleagues provides important novel insights on the role of IL-1F cytokine members in hepatic steatosis and steatohepatitis. It still has to be figured out which IL-1 sources are of key relevance in this and other experimental models of NAFLD as extrahepatic sources could critically contribute to hepatic and overall systemic inflammation (Fig. 1). This work has been supported by the Christian-Doppler Research Society. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic miceJournal of HepatologyVol. 55Issue 5PreviewThe identification of the cellular and molecular pathways that mediate the development of non-alcoholic steatohepatitis is of crucial importance. Cytokines produced by liver-resident and infiltrating inflammatory cells, play a pivotal role in liver inflammation. The role of the proinflammatory cytokines IL-1α and IL-1β in steatohepatitis remains elusive. Full-Text PDF Corrigendum to "IL-1 cytokine family members and NAFLD: Neglected in metabolic liver inflammation" [J Hepatol 2011;55:960–962]Journal of HepatologyVol. 56Issue 3PreviewOn the last page of the article, the name of Dr. Kamari is incorrectly spelled twice as Kumari. This should be changed to Kamari. 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