Protein Tyrosine Phosphatase non-Receptor Type 2 regulates IFN-γ-induced cytokine signaling in THP-1 monocytes
Version of Record online: 28 JUN 2010
Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 16, Issue 12, pages 2055–2064, December 2010
How to Cite
Scharl, M., Hruz, P. and McCole, D. F. (2010), Protein Tyrosine Phosphatase non-Receptor Type 2 regulates IFN-γ-induced cytokine signaling in THP-1 monocytes. Inflamm Bowel Dis, 16: 2055–2064. doi: 10.1002/ibd.21325
- Issue online: 19 NOV 2010
- Version of Record online: 28 JUN 2010
- Manuscript Accepted: 22 MAR 2010
- Manuscript Received: 15 MAR 2010
- 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. PHS grant. Grant Number: DK080506
- intestinal inflammation;
- cytokine signaling
We have previously shown that the Crohn's disease (CD)-associated gene protein tyrosine phosphatase non-receptor Type 2 (PTPN2) regulates interferon gamma (IFN-γ)-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-γ, play an important pathophysiological role in this disease. Here we studied the role of PTPN2 in the regulation of IFN-γ-induced signaling in THP-1 monocytic cells.
Protein analysis was performed by Western blotting, PTPN2 knockdown was induced by siRNA, and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA).
We demonstrated that IFN-γ (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-γ-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-γ-induced secretion of the proinflammatory cytokines interleukin-6 (IL-6) and macrophage chemoattractant protein 1 (MCP-1).
Our data demonstrate that IFN-γ enhances PTPN2 protein in THP-1 cells and loss of PTPN2 promotes IFN-γ-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. (Inflamm Bowel Dis 2010)