PTPN2 Regulates Inflammasome Activation and Controls Onset of Intestinal Inflammation and Colon Cancer

Abstract

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.

Relationship between serum 25‐hydroxyvitamin D3levels and severity of chronic periodontitis in type 2 diabetic patients: A cross‐sectional study

“…Therefore, further evaluations are needed to reveal the precise associations. Nevertheless, given the key role of VD 3 ‐PTPN2 in the response to inflammation, our results further support the previous suggestion that the therapeutic use of agents with anti‐cytokine properties such as VD 3 may provide outstanding benefits in the prevention and treatment of diabetic periodontitis.…”

“…The elevated levels of VDR and PTPN2 expression after VD 3 treatment could result in the downregulation of downstream proinflammatory proteins such as NF‐κB . The PTPN2 gene inhibits the expression of many proinflammatory genes by blocking JAK/STAT‐dependent signaling . Based on our previous animal studies, the present results further confirm the downregulated expression of PTPN2 and VDR in the gingival tissues of T2DCP patients, which could be considered as a pathophysiological effect of 25(OH)D 3 deficiency.…”

Deletion of Protein Tyrosine Phosphatase Nonreceptor Type 2 in Intestinal Epithelial Cells Results in Upregulation of the Related Phosphatase Protein Tyrosine Phosphatase Nonreceptor Type 23

“…3j). This is in line with our previous finding that the regulation of IL-1β and IL-18 via PTPN2 is mediated via changes in protein activation, and not via changes in mRNA levels [18]. …”

“…We have previously shown that loss of PTPN2 promotes activation of inflammasomes [18], and subsequent secretion of IL-1β and IL-18. Therefore, we also addressed whether loss of PTPN2 in epithelial cells affects expression of Il1b and Il18 mRNA.…”

“…For this aim, wt mice and PTPN2xVilCre littermates were subjected to a commonly used mouse model for colorectal carcinoma, namely, the AOM/DSS induced colon tumor model [19]. This treatment resulted in colon inflammation and tumor development as previously described in Spalinger et al [18]. In this experiment, colon tissue pieces from nontumor tissue and from tumor tissue have been collected for mRNA analysis and we here investigated the expression levels of Ptpn2 , Ptpn1 , Ptpn9 , Ptpn11 , Ptpn22 , Ptpn23 , Il1b, and Il18 mRNA.…”