| First Author | Zirnheld AL | Year | 2019 |
| Journal | J Leukoc Biol | Volume | 106 |
| Issue | 6 | Pages | 1349-1358 |
| PubMed ID | 31568613 | Mgi Jnum | J:282728 |
| Mgi Id | MGI:6379112 | Doi | 10.1002/JLB.3A0919-244R |
| Citation | Zirnheld AL, et al. (2019) beta-Catenin stabilization in NOD dendritic cells increases IL-12 production and subsequent induction of IFN-gamma-producing T cells. J Leukoc Biol 106(6):1349-1358 |
| abstractText | Dendritic cells (DC) from diabetes-prone NOD mice and patients with type 1 diabetes (T1D) produce excess IL-12 that drives development of beta-cell-destroying IFN-gamma-producing T cells. The molecular mechanisms that control IL-12 production in T1D are unclear. In this study, we report that beta-catenin, a multifunctional protein involved in inflammation, is dramatically increased in DC from NOD mice. We further investigated the mechanisms leading to accumulation of beta-catenin in NOD DC and its role in the inflammatory pathogenic responses associated with T1D. Hyperphosphorylation of beta-catenin at a stabilizing residue, serine 552, mediated by activation of Akt, appears to lead to beta-catenin accumulation in NOD DC. Elevated beta-catenin in DC correlated with IL-12 production and induction of IFN-gamma-producing CD4 cells. On the one hand, knockdown/inhibition of beta-catenin significantly reduced NOD DC production of IL-12 and their ability to induce IFN-gamma-producing CD4 cells. On the other hand, overexpression of beta-catenin in control DC resulted in increased IL-12 production and induction of IFN-gamma-production in T cells. Additionally, we found that beta-catenin inhibitors decreased NF-kappaB activation in NOD DC and IFN-gamma production by NOD T cells in vivo. These data strongly suggest that accumulation of beta-catenin in DC from NOD mice drives IL-12 production, and consequently, development of pathogenic IFN-gamma-producing T cells. Targeting the defect responsible for beta-catenin accumulation and subsequent overproduction of pro-inflammatory cytokines by NOD DC could be an effective therapeutic strategy for the prevention and/or treatment of T1D. |
