Sodium arsenite reduces severity of dextran sulfate sodium-induced ulcerative colitis in rats

T cell protein tyrosine phosphatase (TC-PTP / PTPN2) is an enzyme that is essential for the proper functioning of the immune system and that participates in the control of cell proliferation, and inflammation. We previously observed that TC-PTP−/− mice display various immunodeficiencies, hypersensitivity to LPS and die within three weeks of birth due to anemia and widespread inflammation. A recent analysis of the Wellcome Trust Case Control Consortium (WTCC) genome wide scan data, reported in 2007, indicated a potential role for TC-PTP in inflammatory bowel disease (IBD). To further investigate the potential role of TC-PTP in IBD, we studied heterozygous TC-PTP mutant mice challenged with dextran sulfate sodium (DSS) in their drinking water. In comparison to control animals, we observed significant changes in the colon mucosa of DSS-treated TC-PTP+/− mice, in the ratio of colon to body weight, as well as an up-regulation of mRNA transcripts for IL-6, IL-23, 1L-12β, IFN-γ, TNF-α. Moreover, up-regulation of serum IL-6 levels in DSS-treated TC-PTP+/− mice confirms that mice with a single copy of the TC-PTP gene display increased susceptibility to systemic inflammation due to bowel epithelial erosion resulting from DSS challenge. Our findings support the lack of modulation of Janus kinases 1 and 3 (Jak1, Jak3), and the downstream signal transducer and activator of transcription 1,3 and 5 (Stat1, Stat3, Stat 5) by PTPN2 in the development of IBD like condition. Pathological and molecular analysis reveal that the deficiency of TC-PTP results in pro-inflammatory condition in the bowel of heterozygous TC-PTP+/− mice. These novel findings in TC-PTP hemi-deficiency support the hypothesis that TC-PTP is an important regulator of inflammatory cytokine signaling and that it may be implicated in the pathophysiology of IBD.

show abstract

“…age 30 days) [15], [16]. Animals were weighed daily and monitored for rectal bleeding, diarrhea, and general signs of morbidity.…”

Section: Methodsmentioning

confidence: 99%

Increased Susceptibility to Dextran Sulfate Sodium Induced Colitis in the T Cell Protein Tyrosine Phosphatase Heterozygous Mouse

et al. 2010

View full text Add to dashboard Cite

show abstract

“…It was calculated in comparison to that of Day 8 before administration of AA. From these data, a disease activity index was calculated as done previously (Malago and Nondoli, 2008) (Table 2).…”

Section: Clinical Evaluation Of Ucmentioning

confidence: 99%

“…After mounting, the slides were observed under a light microscope (Olympus BX41, Olympus, Japan). Two independent pathologists assessed and quantitated in a blind manner the mucosal integrity for histological evaluation of tissue damage as done previously (Malago and Nondoli, 2008). The evaluation was done on distal colon using a 0-3 scoring scale as shown in Table 3.…”

Section: Evaluation Of Histological Changesmentioning

confidence: 99%

“…Blood can also be seen on rectal examination and varying degrees of abdominal pain ranging from mild discomfort to painful bowel movements and/or abdominal cramping during bowel movements may accompany the disease (Torpy et al, 2012). Morphologically, UC is mainly characterized by open sores or ulcers in the colon, loss of epithelium and goblet cells, and infiltration of colonic mucosa by inflammatory cells (Malago and Nondoli, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Continual activation of the immune system to produce proinflammatory chemokines like interleukin (IL)-8 and their subsequent attraction of inflammatory cells that infiltrate the colon mucosa are cascade events that cause the chronic inflammation and ulceration of the colonic epithelium (Malago and Nondoli, 2008;Ke et al, 2013;Liu et al, 2013). The production of these pro-inflammatory cytokines is mediated mainly by transcriptional activation of nuclear factor κB (NF-κB) and mitogen activated protein kinase (MAPK) pathways (Malago et al, 2002;Ke et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Intraperitoneal administration of butyrate prevents the severity of acetic acid colitis in rats

Malago

Sangu²

2015

J. Zhejiang Univ. Sci. B

Self Cite

View full text Add to dashboard Cite

Intrarectal infusion of butyrate improves colorectal disorders including ulcerative colitis (UC). However, it is not established whether systemically administered butyrate benefits such patients. The current study aimed at exploring and comparing the potential of intraperitoneally, intrarectally, and orally administered butyrate against acetic acid (AA)-induced UC in rats. Intrarectal administration of 2 ml of 50% AA was done after or without prior treatment of rats for 7 consecutive days with 100 mg/kg sodium butyrate (SB) intraperitoneally, intrarectally, or orally. Rats were sacrificed after 48 h of AA-treatment. Subsequently, colon sections were processed routinely for histopathological examination. We clinically observed diarrhea, loose stools, and hemoccult-positive stools, and histologically, epithelial loss and ulceration, crypt damage, goblet cell depletion, hemorrhage, and mucosal infiltration of inflammatory cells. The changes were significantly reduced by intraperitoneal, intrarectal, or oral butyrate, with intraperitoneal butyrate exhibiting the highest potency. It is concluded that intraperitoneal administration of butyrate abrogates the lesions of AA-induced UC and its potency surpasses that of intrarectal or oral butyrate.

show abstract

Activation of integrated stress response pathway regulates IL‐1β production through posttranscriptional and translational reprogramming in macrophages

et al. 2019

View full text Add to dashboard Cite

Immune cells sense and programme its cellular machinery appropriately to the environmental changes through the activation of cytoprotective adaptive pathway so-called the "integrated stress response (ISR)". However, the mechanisms implicated in ISR-induced protective responses are poorly understood. Here, we show that ISR activation by arsenite (Ar) results in suppression of IL-1β production in macrophages and inhibition of DSSinduced colitis in a murine model through a novel posttranscriptional and translation regulatory (PTR) mechanism. Ar triggers PTR events through eIF2α-phosphorylation, which results in the attenuation of active polysome formation leading to the accumulation of translationally stalled IL-1β mRNAs. Translationally stalled IL-1β mRNAs recruit RNAbinding proteins (TIA-1/TIAR), resulting in the formation of RBP-RNA complexes known as stress granules (SGs). The SGs bound IL-1β mRNAs might undergo degradation through induction of autophagy. Also, we show that Ar posttranslationally impairs processing and secretion of IL-1β by diminishing inflammasome activation. Altogether, this study unveils a novel mechanism of IL-1β regulation and further suggests that pharmacological activation of cytoprotective ISR pathway might provide an effective therapeutic intervention against inflammatory diseases.Keywords: arsenite r autophagy r integrated stress response (ISR) pathway r stress granules r TIA-1/TIAR Additional supporting information may be found online in the Supporting Information section at the end of the article.

show abstract

Sodium arsenite reduces severity of dextran sulfate sodium-induced ulcerative colitis in rats

Cited by 17 publications

References 26 publications

Increased Susceptibility to Dextran Sulfate Sodium Induced Colitis in the T Cell Protein Tyrosine Phosphatase Heterozygous Mouse

Increased Susceptibility to Dextran Sulfate Sodium Induced Colitis in the T Cell Protein Tyrosine Phosphatase Heterozygous Mouse

Intraperitoneal administration of butyrate prevents the severity of acetic acid colitis in rats

Activation of integrated stress response pathway regulates IL‐1β production through posttranscriptional and translational reprogramming in macrophages

Contact Info

Product

Resources

About