Michael Scharl1, Petr Hruz, Declan F McCole. 1. Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California, USA.
Abstract
BACKGROUND: 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. 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-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). CONCLUSIONS: 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.
BACKGROUND: 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. 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-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). CONCLUSIONS: 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.
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