Autor:innen:
L. Knedla (Gießen, DE)
M. Roderfeld (Gießen, DE)
V. von Bülow (Gießen, DE)
H. Müller (Gießen, DE)
A. Tschuschner (Gießen, DE)
F. Stettler (Gießen, DE)
M. Hagen (Gießen, DE)
S. Riebeling (Gießen, DE)
C. Grevelding (Gießen, DE)
E. Roeb (Gießen, DE)
Introduction: Schistosomiasis is a neglected tropical disease affecting over 240,000,000 people worldwide (*1,*2). Paired adult worms living in the mesenteric vein system produce about 300 eggs daily, eventually provoking granulomatous liver fibrosis. c-Jun, a transcription factor that is involved in hepatocellular regeneration, proliferation, and apoptosis, can be permanently induced in hepatocytes by S. mansoni infection (*3). We aimed to characterize the effects of pharmaceutical inhibition of c-Jun in S. mansoni-infected mice.
Methods: Twelve eight-week-old C57BL/6-mice were each infected with 100 cercariae (♂+♀), while nine non-infected littermates served as controls and supercontrols. Six weeks post-infection, mice were either supplied with the JNK-inhibitor SP600125 (*4) (n = 6; SP/Sm) or 0.9% NaCl (n = 6; Sm). Nine weeks post-infection, organs were harvested. Hepatic damage as well as biomolecular alterations were examined by Western Blotting, RT-qPCR, immunostaining, and functional tests. Differences were statistically analysed via one-way-ANOVA or t-test (SPSS29.0.0.0).
Results: Serum-ALT levels significantly increased in infected mice (130U/L) compared to non-infected controls (30U/L; p < 0.001), and the level enhanced following JNK-inhibition (165U/L, p < 0.05). Concurrently, de-Ritis-ratio decreased under JNK-inhibition compared to S. mansoni-infection (p = 0.067). Furthermore, mice with high transaminase-levels showed a stronger decrease of energetic metabolites like liver-glycogen (p < 0.05), serum-triglycerides (p = 0.074) and related key-enzymes. A stronger impairment of fatty acid synthase was detected under JNK-inhibition (p < 0.05). Similarly, HepG2 cells showed decreasing protein content of glycogenkinase in Western Blotting after coapplication of SP600125 and soluble egg antigens (SEA) compared to SEA (p < 0.05). Apart from metabolic dysregulation, levels of TH2- (IL4, IL6, IL13, p < 0.05), TH1- (CXCL9 p < 0.05), immune cell differentiation-related cytokines (IL2, IL5 p < 0.01; CXCL2 p < 0.05), and downstream factors like phosphorylated STAT3 (p < 0.05) increased under inhibitor-application, providing a possible explanation for increased requirement and exhaustion of energetic metabolites in the mice liver tissue.
Conclusion: The current results suggest that the inhibition of JNK/c-Jun-signalling with SP600125 in S. mansoni-infected mice alters metabolism and immune response, leading to more severe hepatocellular exhaustion and damage.