A novel approach to ameliorate liver inflammation and disease progression in a murine model of chronic liver disease
Nadine Hermanns1, Francisco Javier Cubero1, Antje Mohs1, Kim Ohl2, Malika Al Masaoudi1, Christian Liedtke1, Klaus Tenbrock2, Christian Trautwein1;
1 Department of Medicine III, RWTH University Hospital, Aachen, Germany;2Department of Pediatrics, Division of Allergology and Immunology, RWTH University Hospital, Aachen, Germany
Background & Aim: The Interleukin-17 (IL-17)-mediated immune response has been shown to play a crucial role in inflammation-associated disease. Actually, serum IL-17 levels have been incorporated in the clinic as a marker of severity of liver injury. Since, the transcription factor cAMP-responsive element modulator (CREM)-α contributes to increased IL-17 expression observed in patients with liver disease, we reasoned whether overexpression of CREM-α has an impact on the initiation and progression of liver fibrosis and hepatocellular carcinoma (HCC). Methods: Transgenic mice overexpressing CREM-α in T-Cells (controlled by CD2 promotor) were crossed with hepato-cyte-specific Nemo knockout (NemoΔhepa) mice, a model of chronic liver injury. Here, the phenotype was characterized during the progression of acute and chronic liver injury. Results: In 8 week old NemoΔhepa/CREM-α compared with NemoΔhepa mice, we found significantly reduced serum AST and ALT levels. These findings were associated with lower absolute numbers of infiltrating CD11 b+ and F4/80 cells in NemoΔhepa /CREM-α livers. In addition, we found significantly elevated mRNA expression levels of cytokines IL-10 and IL-4 in both T-cells and liver tissue in NemoΔhepa/CREM-α compared with NemoΔhepa and WT mice suggesting that the CREM-α transgene in T-cells influences liver inflammation towards a protective environment. Liver histology and sirius red staining revealed that fibrosis was significantly reduced in NemoΔhepa/CREM-α compared to NemoΔhepa livers in 13 weeks old animals. This was further confirmed by studying extracellular matrix deposition showing significantly reduced Collagen IA1 and fiber deposition in NemoΔhepa/CREM-α livers, which was accompanied by decreased desmin-associated activation of Hepatic Stellate cells. In 52 weeks old NemoΔhepa/CREM-α livers, a significantly reduced liver-body-weight ratio and significantly less nodules in comparison to
NemoΔhepa mice were evident. Additionally, c-myc mRNA levels and protein levels of glutamine synthetase revealed lower cancer related-metabolism in NemoΔhepa/CREM-α livers. Conclusion: Our results demonstrate that overexpression of CREM-a in T-cells in NemoΔhepa mice attenuates disease progression as shown by reduced liver fibrosis and growth of HCC. This finding is the result of changing inflammation in these livers towards a protective milieu by enhancing the expression of distinct cytokines (IL-4, IL-10) and by reducing immune cell infiltration and IL-17 production. The present findings suggest a new molecular approach to reduce disease progression in chronic liver diseases.
Christian Trautwein - Grant/Research Support: BMS, Novartis, BMS, Novartis; Speaking and Teaching: Roche, BMS, Roche, BMS
The following people have nothing to disclose: Nadine Hermanns, Francisco Javier Cubero, Antje Mohs, Kim Ohl, Malika Al Masaoudi, Christian Liedtke, Klaus Tenbrock