Interleukin-35 Attenuates D-Galactosamine/Lipopolysaccharide-Induced Liver Injury via Enhancing Interleukin-10 Production in Kupffer Cells

Abstract

Interleukin (IL) -35 is an anti-inflammatory cytokine which exerts various beneficial effects on autoimmune diseases. However, whether IL-35 plays a role in endotoxin induced hepatitis demands clarification. This study aims to reveal the effect and mechanism of IL-35 on endotoxin induced liver injury. Acute hepatic injury was induced by D-galactosamine (D-GalN, 400 mg/kg) and lipopolysaccharide (LPS, 5 μg/kg) administration in mice. IL-35 treatment ameliorated D-GalN/LPS induced liver injury in a dose dependent manner as shown by histological examination, ALT determination and Caspase-3 activity assay. It also reduced production of pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, IL-1β, and IL-6, and increased production of anti-inflammatory cytokines, IL-4, IL-10, and transforming growth factor (TGF)-β. This hepato-protective effect was proved mainly mediated by Kupffer cells (KC) via gadolinium chloride depletion and cell adoptive transfer experiment. In addition, IL-35 emolliated the cytotoxicity of LPS-triggered KCs to hepatocytes, suppressed nitric oxide (NO) and TNF-α production, and elevated IL-10 production in LPS stimulated KCs. Furthermore, IL-35 could not exert hepato-protective effect in IL-10-deficient mice in vivo and it could not suppress LPS induced NO and TNF-α production in IL-10-deficient KCs in vitro. In conclusion, IL-35 protects endotoxin-induced acute liver injury, which mainly acts thought increasing IL-10 production in KCs. This finding demonstrates a role of IL-35 in anti-infectious immunity and provides a potential therapeutic target in treating fulminant hepatitis.

Role of macrophages in experimental liver injury and repair in mice (Review)

“…Furthermore, increasing the production of IL-10 in macrophages via treatment with IL-35 also provided a therapeutic effect (94).…”

Interleukin-35 pretreatment attenuates lipopolysaccharide-induced heart injury by inhibition of inflammation, apoptosis and fibrosis

“…The present study is the first to show that IL-35 pretreatment significantly attenuated LPS-induced heart proinflammatory responses, as evidenced by the decreased production of proinflammatory cytokines in the serum, heart tissues and cultured CFs. The effects of IL-35 on production of the anti-inflammatory cytokine IL-10 are controversial (23,27,28). In this study, we did not observe any effects of IL-35 on the levels of the anti-inflammatory cytokine IL-10 in mouse heart tissue and serum ( Figure 3L, and M), suggesting that the anti-inflammatory properties of IL-35 are not dependent on IL-10.…”

“…IL-35 has been reported to have several important functions, such as anti-inflammatory, anti-oxidative, and anti-apoptotic properties. IL-35 protected against acute liver and kidney injury caused by LPS through inhibiting inflammatory responses (27,28). IL-35 also inhibited lysophosphatidylcholine-induced mitochondrial reactive oxygen species (mtROS) production and human aortic endothelial activation (29,30).…”

Interleukin-35 has a tumor-promoting role in hepatocellular carcinoma

“…IL‐35 has been reported to play a role in liver disease, including viral hepatitis, hepatic fibrosis, liver cirrhosis and chemical‐induced liver injury, as well as HCC [10,24–28]. A large amount of HCC is associated with impairment of the proliferation, cytokine production and cytotoxic effector functions accompanied by a chronic hepatitis virus‐specific T cell immune reaction [29].…”