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Hepatitis C Virus (HCV) infection promotes hepatocyte proliferation, which can progress to hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) involved in signaling pathways for proliferation and apoptosis are altered upon HCV infection. miR-181c was shown to be down-regulated in HCV-infected hepatocytes. Patra et al. now show that miR-181c targets a protein kinase, ataxia-telangiectasia mutated (ATM), which is involved in repairing DNA damage to enhance cell survival. HCV-infected hepatocytes and patient liver tissue exhibited higher ATM and lower miR-181C expression. Enhanced ATM results in protein kinase B (Akt) activation, which then phosphorylates a key cell-cycle regulator, cyclin-dependent kinase-2 (Cdk2). Exogenous expression of miR-181c suppresses Akt activation, down-regulates Cdk2 phosphorylation, and causes cell-cycle arrest in the G 2 phase. Attenuation in cell cycle was associated with apoptosis in hepatocytes. Consistent with these observations, miR-181c promoted apoptosis in xenograft tumors, thereby regressing tumor growth in a xenograft mouse model. The antiproliferative effects of miR-181C suggests a treatment potential for HCV-associated liver disease progression. (Hepat ology 2019;71:780-793).

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Background Significant proportion of inflammatory bowel disease (IBD) patients respond inconsistently to therapies, underscoring disease complexity. Interleukin 21 (IL21) is highly expressed during IBD. In addition to T helper (Th) cells, inflammatory regulatory T cells (Tregs) have been linked to refractory IBD. Thus, we explored the metabolic role of IL21 in inducing Treg dysfunction and IBD. Methods Human Tregs and Th cells were subjected to transcriptional profiling and metabolic phenotyping. Colitis was induced in Rag1−/− mice by naïve CD4 T cell adoptive transfer. Results IL21 stimulation of human Tregs induced glycolysis and OXPHOS. In agreement, IL21 enhanced the expression of genes associated with glycolysis, anabolism, and OXPHOS, leading to inflammatory cytokine production. Mechanistically, we found disruption to mitochondrial integrity with concomitant activation of glycogen synthase kinase 3 (GSK3) β, a kinase known to prevent mitochondrial pyruvate metabolism. IL21-induced GSK3β activation was accompanied by pyruvate and lactate buildup. Notably, GSK3 inhibition or supplementation with membrane-permeable methyl pyruvate abrogated metabolic wiring of and inflammatory responses by IL21-stimulated Tregs and effector Th cells. These results suggest that impaired mitochondrial pyruvate metabolism is a feature of inflammatory CD4 T cells. Lastly, GSK3 inhibition prevented pathogenic CD4 T cell-induced colitis in mice, as evidenced by reduced Mouse Colon Histology Index and serum inflammatory cytokines. Conclusions IL21 engages Tregs in a hypermetabolic state that augments inflammatory cytokine production. Therefore, desensitizing CD4 T cells to IL21 may also augment Treg function during IBD. Supported by NIDDK award K01DK124358, the Center for Cell Signaling in Gastroenterology (P30DK084567), and the Mayo Clinic Center for Biomedical Discovery.

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