Activation of Protein Tyrosine Phosphatase Non-Receptor Type 2 by Spermidine Exerts Anti-Inflammatory Effects in Human THP-1 Monocytes and in a Mouse Model of Acute Colitis

Abstract

BackgroundSpermidine is a dietary polyamine that is able to activate protein tyrosine phosphatase non-receptor type 2 (PTPN2). As PTPN2 is known to be a negative regulator of interferon-gamma (IFN-γ)-induced responses, and IFN-γ stimulation of immune cells is a critical process in the immunopathology of inflammatory bowel disease (IBD), we wished to explore the potential of spermidine for reducing pro-inflammatory effects in vitro and in vivo.MethodsHuman THP-1 monocytes were treated with IFN-γ and/or spermidine. Protein expression and phosphorylation were analyzed by Western blot, cytokine expression by quantitative-PCR, and cytokine secretion by ELISA. Colitis was induced in mice by dextran sodium sulfate (DSS) administration. Disease severity was assessed by recording body weight, colonoscopy and histology.ResultsSpermidine increased expression and activity of PTPN2 in THP-1 monocytes and reduced IFN-γ-induced phosphorylation of signal transducer and activator of transcription (STAT) 1 and 3, as well as p38 mitogen-activated protein kinase (MAPK) in a PTPN2 dependent manner. Subsequently, IFN-γ-induced expression/secretion of intracellular cell adhesion molecule (ICAM)-1 mRNA, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6 was reduced in spermidine-treated cells. The latter effects were absent in PTPN2-knockdown cells. In mice with DSS-induced colitis, spermidine treatment resulted in ameliorated weight loss and decreased mucosal damage indicating reduced disease severity.ConclusionsActivation of PTPN2 by spermidine ameliorates IFN-γ-induced inflammatory responses in THP-1 cells. Furthermore, spermidine treatment significantly reduces disease severity in mice with DSS-induced colitis; hence, spermidine supplementation and subsequent PTPN2 activation may be helpful in the treatment of chronic intestinal inflammation such as IBD.

Comparative Evaluation between Sulfasalazine Alone and in Combination with Herbal Medicine on DSS-Induced Ulcerative Colitis Mice

“…These protein levels were downregulated to nearly normal levels ( Figure 6 ). MCP-1 promotes monocyte infiltration into inflamed tissues and elevated levels of MCP-1 can be found in the intestinal mucosa of IBD patients [ 38 ]. Accordingly, reduced MCP-1 by SBC treatment might reduce the attraction of inflammatory cells into the intestine and thereby decrease inflammatory responses ( Figure 6 ).…”

The Mucosal Immune System and Its Regulation by Autophagy

“…For instance, the autophagy-enhancing drug carbamazepine has been shown to ameliorate hepatic fibrosis in the mouse model of α1-antitrypsin deficiency liver cirrhosis, and this drug is currently in phase II of clinical trials ( 333 , 334 ). Additionally, an autophagy-inducing agent has been shown to decrease pathology in a mouse model of chemically induced colitis ( 335 , 336 ). The challenge, however, is to identify agents that can specifically induce autophagy with minimal side effects on other cellular processes.…”

Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity

“…The SNP rs12969241 in the PTPN2 gene was also among the top in the GWAS of cholestatic pattern of DILI ( P = 6.8 × 10 −6 ) (Additional file 1 : Table S3). The protein encoded by the PTPN2 gene is an intracellular tyrosine-specific phosphatase, which is expressed in epithelial cells, fibroblasts or endothelial cells [ 33 ]. This protein was shown to play an important role in the protection of epithelial barrier function during inflammation by acting as negative regulator of pro-inflammatory cytokine interferon-γ [ 34 ].…”