Immunotherapy for nonalcoholic steatohepatitis using themultiple cytokine production modulator Y-40138

Abstract

AIM:To investigate the possible use of the multiple cytokine production modulator, Y-40138, as a novel immunotherapy in the rat nonalcoholic steatohepatitis (NASH) model. METHODS:We allocated 6-wk-old male F344 rats to choline-supplemented, L-amino acid-defined (CSAA) diet (control group), CSAA diet + Y-40138 (control + Y-40138 group), choline-deficient, L-amino acid-defined (CDAA) diet (NASH group), or CDAA diet + Y-40138 (NASH + Y-40138 group). In each group, we measured the plasma alanine aminotransferase (ALT) levels, and the plasma and liver levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-10 (IL-10). Tissue specimens of phosphate buffered saline-perfused liver were subjected to hematoxylin and eosin staining, Azan staining, Sirius red staining, and immunohistochemical staining (for Kupffer cells and TNF-α). We then extracted Kupffer cells from the collagenase-perfused livers using the Percoll gradient centrifugation method, and measured the TNF-α levels in the supernatant (in vitro TNF-α production by Kupffer cells) using an enzyme-linked immunosorbent assay kit. RESULTS:In comparison to the NASH group, serum ALT elevation was mild, production of serum and liver TNF-α and IFN-γ was inhibited, and IL-10 production was increased in the NASH + Y-40138 group. Amelioration of liver histology was also noted in the NASH + Y-40138 group. Kupffer cell immunohistochemical staining revealed no differences between groups, whereas TNF-α immunohistochemical staining showed fewer stained cells in the NASH + Y-40138 group than in the NASH group. The TNF-α levels in the in-vitro Kupffer cell culture supernatant were lower in the NASH + Y-40138 group than in the NASH group. CONCLUSION:Administration of Y-40138 to NASH model rats reduced hepatic inflammation and suppressed fibrosis. These results indicate that the multiple cytokine production modulator, Y-40138, is promising as a novel treatment for NASH.

Innate Immune Reactivity of the Ileum–Liver Axis in Nonalcoholic Steatohepatitis

“…In NASH, for which the histological picture is similar to that for ALD, activation of Kupffer cells by LPS to produce inflammatory cytokines is thought to cause inflammation within the hepatic lobules [14]. In fact, elevated levels of TNF-a are seen in the peripheral blood and hepatic tissues in patients with NASH [4]. Lifestyle factors, for example bulimia or unbalanced diet, can impose an excessive metabolic burden on the hepatocytes, and simultaneously induce qualitative and quantitative abnormalities in the intestinal flora.…”

“…NASH develops when simple steatosis is first complicated by fatty degeneration because of insulin resistance, followed by aggravating factors including inflammatory cytokines, for example tumor necrosis factor a (TNF-a), oxidative stress, and endotoxins (Et) [1]. Kupffer cells, part of the innate immunity system, produce various cytokines and are known to be involved in the pathogenesis of liver diseases [2], and functional abnormalities of Kupffer cells and the innate immunity system are probably involved in NASH [3,4]. Although the etiological mechanisms of NASH have not been fully elucidated, similar histopathological findings in NASH and alcoholic hepatitis suggest a common underlying mechanism.…”

An improved mouse model that rapidly develops fibrosis in non‐alcoholic steatohepatitis

“…Therefore, a rat model fed the CDAA diet is considered to be a suitable animal model with which to examine potential therapeutic agents, such as multiple cytokine modulators (Tsujimoto et al . 2009) and anti-platelet drugs (Fujita et al . 2008).…”

Toll‐like receptor‐4 signalling in the progression of non‐alcoholic fatty liver disease induced by high‐fat and high‐fructose diet in mice

“…The findings that hepatic steatosis is markedly reduced in TLR4 mut mice demonstrate that the TLR4 signalling pathway plays a crucial role in the initiation of liver steatosis. Following activation by its ligands, TLR4 has been shown to trigger NF‐ κ B activation and proinflammatory cytokine production and release by recruiting the common TLR adaptor MyD88, as well as by an alternative MyD88‐independent pathway in alcohol‐induced liver inflammation and injury . Recently, IRF3 and IRF7 were reported to take part in high‐fructose diet‐induced NALFD .…”

“…In addition, activation of the TLR4 signalling pathway may be perturbed at multiple steps during the initiation and progression of NAFLD . Upon activation of the TLR4 signalling pathway, the release of a large array of inflammatory cytokines is significantly increased, including tumour necrosis factor (TNF)‐ α , interleukin (IL)‐1 β , IL‐6 and IL‐12, together with the anti‐inflammatory cytokine IL‐10 . Activation of TLR4 not only potentiates the production of various chemokines, thereby inducing chemotaxis of Kupffer cells, but also mediates the development of liver fibrosis by inhibiting the transforming growth factor (TGF)‐ β pseudoreceptor Bambi, which can sensitize hepatic stellate cells (HSC) to TGF‐ β signals .…”