Hepatic overexpression of cAMP-responsive element modulator α induces a regulatory T-cell response in a murine model of chronic liver disease

OBJECTIVE: Th17 cells are a subset of CD4(+) T-helper cells characterised by interleukin 17 (IL-17) production, a cytokine that plays a crucial role in inflammation-associated diseases. The cyclic AMP-responsive element modulator-α (CREMα) is a central mediator of T-cell pathogenesis, which contributes to increased IL-17 expression in patients with autoimmune disorders. Since an increased Th17 response is associated with a poor prognosis in patients with chronic liver injury, we investigated the relevance of Th17 cells for chronic liver disease (CLD) and hepatocarcinogenesis. DESIGN: Transgenic mice overexpressing CREMα were crossed with hepatocyte-specific Nemo knockout mice (Nemo(Δhepa)) to generate Nemo(Δhepa)/CREMα(Tg) mice. The impact of CREMα(Tg) on CLD progression was examined. Additionally, soft agar colony formation assays, in vitro studies, adoptive transfer of bone marrow-derived cells (BMDCs) and T cells, and gene arrays in T cells were performed. RESULTS: 8-week-old Nemo(Δhepa)/CREMα(Tg) mice presented significantly decreased transaminase levels, concomitant with reduced numbers of CD11b(+) dendritic cells and CD8(+) T cells. CREMα(Tg) overexpression in Nemo(Δhepa) mice was associated with significantly reduced hepatic fibrogenesis and carcinogenesis at 52 weeks. Interestingly, hepatic stellate cell-derived retinoic acid induced a regulatory T-cell (Treg) phenotype in CREMα(Tg) hepatic T cells. Moreover, simultaneous adoptive transfer of BMDCs and T cells from CREMα(Tg) into Nemo(Δhepa) mice ameliorated markers of liver injury and hepatitis. CONCLUSIONS: Our results demonstrate that overexpression of CREMα in T cells changes the inflammatory milieu, attenuating initiation and progression of CLD. Unexpectedly, our study indicates that CREMα transgenic T cells shift chronic inflammation in Nemo(Δhepa) livers towards a protective Treg response.