Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. Activation of macrophages and hepatic stellate cells is a critical step that promotes liver fibrosis. We aimed to explore the feasibility of interleukin-34 (IL-34), a key regulator of macrophages, as a fibrosis marker in patients with NAFLD. We enrolled 197 liver biopsy-proven NAFLD patients. We evaluated the serum levels of IL-34, macrophage-colony stimulating factor (M-CSF), soluble CD163 (sCD163), 40 cytokines/chemokines, hyaluronic acid, type IV collagen 7s, and clinically-approved fibrosis scores. IL-34 increased with the progression of fibrosis and was an independent marker for liver fibrosis. Immunostaining experiments, using resected liver specimens from NAFLD patients, revealed that IL-34 was mainly expressed on liver fibroblasts. IL-34 based fibrosis score (0.0387*IL-34 (pg/ml) + 0.3623*type IV collagen 7s (ng/ml) + 0.0184*age (year)–1.1850) was a practical predictive model of liver fibrosis. Using receiver-operating characteristic analyses, the area under the curve, sensitivity, and specificity of IL-34 based fibrosis score were superior or comparable to the other fibrosis biomarkers and scores. In conclusion, the IL-34 based fibrosis score, including serum IL-34, type IV collagen 7s and age, is a feasible diagnostic marker of liver fibrosis in NAFLD patients.

Interleukin‐34 mediated by hepatitis B virus X protein via CCAAT/enhancer‐binding protein α contributes to the proliferation and migration of hepatoma cells

“…12,13 Currently, the expression of IL-34 is identified as increase in patients with infection of various viruses, including HIV, 33 influenza A virus 34 and HCV. 35 15 Importantly, the increased IL-34 was associated with liver inflammation and fibrosis in HBV infection, and the results were consistent with the phenomenon observed in non-alcoholic fatty liver disease and chronic hepatitis C. 35,36 Besides these, IL-34 is shown to increase in different tumour cells, 26,[37][38][39] and related to the prognosis of various cancers. In addition, Zhou S et al showed that the upregulation of IL-34 contributed the development of HCC.…”

High serum interleukin‐34 level is a predictor of poor prognosis in patients with non‐viral hepatocellular carcinoma

“…Prothrombin activity and FIB‐4 index are markers for liver function and hepatic fibrosis, respectively. We previously reported an association between hepatic fibrosis and serum IL‐34 level in patients with NAFLD . In this study, the prevalence of Child–Pugh class B and C was high in the high IL‐34 group compared to the low IL‐34 group (data not shown).…”

“…We previously reported an association between hepatic fibrosis and serum IL-34 level in patients with NAFLD. 12 In this study, the prevalence of Child-Pugh class B and C was high in the high IL-34 group compared to the low IL-34 group (data not shown). Preisser et al reported that, in patients with HCV or HBV infection, injured hepatocytes secrete IL-34, which induces monocyte recruitment and differentiation into profibrogenic macrophages, as well as promoting type I collagen secretion by hepatic stellate cells.…”

“…We previously reported that interleukin‐34 (IL‐34) and YKL‐40 are associated with hepatic fibrosis in patients with non‐alcoholic fatty liver disease (NAFLD), which is one of the major etiologies of non‐viral HCC. Interleukin‐34, a fibroblast‐derived cytokine, promotes collagen synthesis by hepatic stellate cells, and elevated serum IL‐34 levels are found in patients with chronic inflammation, including obesity, and insulin resistance . Interleukin‐34 is also involved in the differentiation and survival of macrophages in response to inflammation .…”

PD-L1+MDSCs are increased in HCC patients and induced by soluble factor in the tumor microenvironment

“…They demonstrated that the increase in MDSCs was only correlated with tumor progression, but not with hepatic fibrosis or the disease activity of chronic liver disease30. On the other hand, other research groups reported that M-CSF was associated with hepatic fibrosis in chronic hepatitis C and non-alcoholic fatty liver disease patients3132. Moreover, they found that M-CSF could be produced from hepatocytes with persistent HCV infection31.…”