Journal
INFLAMMATORY BOWEL DISEASES
Volume 16, Issue 12, Pages 2055-2064Publisher
OXFORD UNIV PRESS INC
DOI: 10.1002/ibd.21325
Keywords
PTPN2; IFN-gamma; MCP-1; intestinal inflammation; cytokine signaling
Categories
Funding
- Crohn's and Colitis Foundation of America (CCFA)
- German Research Foundation (DFG)
- Swiss National Foundation (SNF)
- Margarete and Walter Lichtenstein Foundation
- UCSD Digestive Diseases Research Development Center, U.S [DK080506]
Ask authors/readers for more resources
Background: We have previously shown that the Crohn's disease (CD)-associated gene protein tyrosine phosphatase nonreceptor Type 2 (PTPN2) regulates interferon gamma (IFN-gamma)-induced signaling and barrier function in intestinal epithelial cells. Overactivation of immature immune cells has been demonstrated in CD and elevated levels of proinflammatory cytokines, such as IFN-gamma, play an important pathophysiological role in this disease. Here we studied the role of PTPN2 in the regulation of IFN-gamma-induced signaling in THP-1 monocytic cells. Methods: Protein analysis was performed by Western blotting, PTPN2 knockdown was induced by siRNA, and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: We demonstrated that IFN-gamma (1000 U/mL) treatment of THP-1 cells elevates PTPN2 protein, reaching a peak by 24 hours. Increased PTPN2 expression, in turn, correlated with decreased activity of the signaling molecules, signal transducer and activator of transcription (STAT) 1 and STAT3. Loss of PTPN2 potentiated IFN-gamma-induced phosphorylation of both of the STATs and of the mitogen-activated protein kinase (MAPK) family member, p38. However, PTPN2 loss did not affect the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 or c-Jun N-terminal kinase. As a functional consequence. PTPN2 knockdown elevated the IFN-gamma-induced secretion of the proinflammatory cytokines interleukin-6 (IL-6) and macrophage chemoattractant protein 1 (MCP-1). Conclusions: Our data demonstrate that IFN-gamma enhances PTPN2 protein in THP-1 cells and loss of PTPN2 promotes IFN-gamma-induced STAT signaling and secretion of IL-6 and MCP-1. Therefore, we show that PTPN2 regulates inflammation-related events and PTPN2 dysregulation may contribute to the onset as well as to the perpetuation of inflammatory events associated with CD.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available