Interleukin‐33/ST2‐Mediated Inflammation Plays a Critical Role in the Pathogenesis and Severity of Type I Autoimmune Hepatitis

Abstract

Interleukin (IL)‐33 was recently described as a new member of the IL‐1 family; members of this family have proinflammatory activity. IL‐33 and its soluble receptor ST2 (sST2) have been implicated in the pathogenesis of autoimmune diseases. This study investigated serum IL‐33 and sST2 in type I autoimmune hepatitis (AIH) and the relationship of these molecules with clinical and pathologic parameters. Subjects included 65 patients with AIH who were diagnosed in our hospital. The control population included 17 healthy individuals and 36 patients with primary biliary cholangitis (PBC). Mean age at AIH diagnosis was 55.5 years, and the male‐to‐female ratio was 6:59. Serum IL‐33 and sST2 levels were significantly higher in patients with AIH than in those with PBC or controls. Importantly, immunohistochemistry revealed high IL‐33 expression in liver sections from patients with AIH. In particular, serum IL‐33 and sST2 levels were significantly higher in acute‐onset AIH than in chronic‐onset AIH. Serum IL‐33 levels were positively correlated with serum total bilirubin (TB), alanine aminotransferase (ALT), and necroinflammatory activity in AIH. We performed multivariate logistic regression analysis and found serum IL‐33 levels to be independent factors for severe activity. Serum sST2 levels were positively correlated with serum TB and ALT and negatively correlated with serum albumin and prothrombin time in AIH. In particular, serum sST2 levels were significantly higher in severe symptoms of AIH. Serum IL‐33 and sST2 levels in patients with AIH responsive to treatment with prednisolone were significantly decreased after treatment. Interestingly, serum IL‐33 level was associated with a significantly increased risk of relapse. Conclusion: IL‐33/ST2 may play an important role in the pathogenesis and severity of AIH and may be a promising target for AIH therapy.

Association of serum 25-hydroxyvitamin D levels with severe necroinflammatory activity and inflammatory cytokine production in type I autoimmune hepatitis

“…Acute-onset AIH accounted for 52% of the cases. Twenty patients (30%) had a severe form of AIH (TB >5.0 mg/dL and/or PT <40%) [ 26 ]; 10 patients (15%) had cirrhosis at diagnosis, and 3 patients (5%) developed cirrhosis. Four patients (6%) developed decompensation.…”

“…The stages of fibrosis were as follows: F0 (6/61, 9.8%), F1 (9/61, 14.8%), F2 (19/61, 31.1%), F3 (19/61, 31.1%), and F4 (8/61, 13.1%). Regarding therapy, most patients (89%) were treated with prednisolone (PSL), and 15 (23%) were treated with azathioprine in combination with PSL [ 26 ].…”

“…On the other hand, IL-33 was recently described as a new member of the IL-1 family, whose members exhibit proinflammatory activity [ 26 ]. Following cellular stress or damage, IL-33 is released in either its full length or cleaved form [ 26 ].…”

“…On the other hand, IL-33 was recently described as a new member of the IL-1 family, whose members exhibit proinflammatory activity [ 26 ]. Following cellular stress or damage, IL-33 is released in either its full length or cleaved form [ 26 ]. However, unlike IL-1β, IL-33 is not cleaved by caspase-1, and its cleavage is not necessary for its secretion, biological activity, or release, further suggesting that IL-33 plays a role as an alarmin [ 26 ].…”

Critical roles of conventional dendritic cells in autoimmune hepatitis via autophagy regulation

“…We then investigated the mechanisms involved in BMDCs maturation in EAH model, which is the recognized animal model of AIH. Accumulating evidence has shown that, in AIH patients and EAH model, the serum levels of LPS, TNF-α and IL-33 were markedly increased compared with that in healthy controls [22][23][24] . To reveal whether those elevated cytokines in AIH patients or EAH model could induce the maturation of BMDCs, im-BMDCs were stimulated in vitro with LPS, TNF-α and IL-33, respectively.…”