Clinic for Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Clinic for Dermatology, University Hospital Zurich, Zurich, Switzerland.
Cell Rep. 2018 Feb 13;22(7):1835-1848. doi: 10.1016/j.celrep.2018.01.052.
Variants in the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with inflammatory disorders, including inflammatory bowel diseases, rheumatoid arthritis, and type 1 diabetes. The anti-inflammatory role of PTPN2 is highlighted by the fact that PTPN2-deficient mice die a few weeks after birth because of systemic inflammation and severe colitis. However, the tissues, cells, and molecular mechanisms that contribute to this phenotype remain unclear. Here, we demonstrate that myeloid cell-specific deletion of PTPN2 in mice (PTPN2-LysMCre) promotes intestinal inflammation but protects from colitis-associated tumor formation in an IL-1β-dependent manner. Elevated levels of mature IL-1β production in PTPN2-LysMCre mice are a consequence of increased inflammasome assembly due to elevated phosphorylation of the inflammasome adaptor molecule ASC. Thus, we have identified a dual role for myeloid PTPN2 in directly regulating inflammasome activation and IL-1β production to suppress pro-inflammatory responses during colitis but promote intestinal tumor development.
编码蛋白酪氨酸磷酸酶非受体型 2（PTPN2）的基因座中的变异与炎症性疾病有关，包括炎症性肠病、类风湿关节炎和 1 型糖尿病。PTPN2 的抗炎作用突出表现在 PTPN2 缺陷型小鼠在出生后几周内因全身性炎症和严重结肠炎而死亡。然而，导致这种表型的组织、细胞和分子机制仍不清楚。在这里，我们证明了小鼠髓系细胞特异性缺失 PTPN2（PTPN2-LysMCre）可促进肠道炎症，但以 IL-1β 依赖的方式保护免受结肠炎相关肿瘤的形成。PTPN2-LysMCre 小鼠中成熟 IL-1β 产生水平升高是由于炎性体衔接分子 ASC 的磷酸化增加导致炎性体组装增加的结果。因此，我们已经确定了髓样 PTPN2 在直接调节炎性体激活和 IL-1β 产生方面的双重作用，以在结肠炎期间抑制促炎反应，但促进肠道肿瘤的发展。
