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Published on: April 21, 2015
Lack of transketolase-like (TKTL) 1 aggravates murine experimental colitis
Susanne Bentz1, Theresa Pesch, Lutz Wolfram
1Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich, Switzerland.
Abstract:
Transketolase-like (TKTL) 1 indirectly replenishes NADPH preventing damage induced by reactive oxygen species (ROS) formed upon intestinal inflammation. We investigated the function of TKTL1 during murine colitis and ROS detoxification for prevention of tissue damage. Mucosal damage in TKTL1(-/-) and wild-type (WT) mice was assessed by miniendoscopy and histology during dextran sodium sulfate (DSS) colitis. mRNA levels of interferon (IFN)-γ, inducible nitric oxide synthase (iNOS), interleukin (IL)-6, tumor necrosis factor (TNF), transketolase (TKT), and TKTL2 were determined by PCR and/or Western blotting. To assess oxidative and nitrosative stress nitrosylation, carbonylation and antioxidative enzymes catalase (Cat), superoxide dismutase 1 and 2, as well as glutathione (GSH) were determined. Myeloperoxidase (MPO) was determined for assessment of tissue neutrophils. TKTL1 knockout or DSS treatment did not influence TKT and TKTL2 mRNA or protein expression. Mucosal damage was significantly increased in TKTL1(-/-) mice indicated by miniendoscopy as well as a significantly shorter colon and more severe histological scores compared with WT mice during DSS colitis. This was associated with higher mRNA levels of IFN-γ, iNOS, IL-6, and TNF. In addition, iNOS protein expression was significantly enhanced in TKTL1(-/-) mice as well as MPO activity. Protein modification by nitric oxide (nitrotyrosine) was induced in TKTL1(-/-) mice. However, introduction of carbonyl groups by ROS was not induced in these mice. The expression of SOD1, SOD2, Cat, as well as GSH content was not significantly changed in TKTL1(-/-) mice. We conclude that induced colitis in TKTL1(-/-) mice was more severe compared with WT. This indicates a role of TKTL1 during mucosal repair and restoration.
Insights
Transketolase-like 1 (TKTL1) deficiency exacerbates intestinal inflammation and tissue damage during colitis. This suggests TKTL1 plays a crucial role in mucosal repair and protecting against reactive oxygen species (ROS).
Area of Science:
- Biochemistry
- Immunology
- Gastroenterology
Background:
- Transketolase-like 1 (TKTL1) is implicated in NADPH replenishment, crucial for mitigating reactive oxygen species (ROS) damage.
- Intestinal inflammation, such as that induced by dextran sodium sulfate (DSS), generates ROS, potentially damaging the gut mucosa.
Purpose of the Study:
- To investigate the functional role of TKTL1 in murine colitis models.
- To determine TKTL1's involvement in ROS detoxification and prevention of intestinal tissue damage.
Main Methods:
- Induction of colitis in TKTL1 knockout (TKTL1(-/-)) and wild-type (WT) mice using DSS.
- Assessment of mucosal damage via miniendoscopy and histology.
- Quantification of inflammatory markers (IFN-γ, iNOS, IL-6, TNF) and oxidative stress indicators (nitrotyrosine, carbonyl groups, MPO, GSH, antioxidant enzymes).
Main Results:
- TKTL1(-/-) mice exhibited significantly increased mucosal damage, shorter colons, and more severe histological scores during DSS colitis compared to WT mice.
- Elevated mRNA levels of IFN-γ, iNOS, IL-6, and TNF were observed in TKTL1(-/-) mice.
- Increased iNOS protein expression and myeloperoxidase (MPO) activity, along with nitrotyrosine formation, were noted in TKTL1(-/-) mice, indicating enhanced nitrosative stress.
Conclusions:
- TKTL1 deficiency leads to more severe experimental colitis, highlighting its protective role in the intestinal mucosa.
- TKTL1 appears essential for mucosal repair and restoration processes during inflammatory conditions.
