Abstract
Reactive oxygen species (ROS) have been implicated in the progression of inflammatory diseases including inflammatory bowel diseases (IBD). Meanwhile, several studies suggested the protective role of ROS in immune-mediated inflammatory diseases, and it was recently reported that dextran sodium sulfate (DSS)-induced colitis was attenuated in mice with an elevated level of ROS due to deficiency of peroxiredoxin II. Regulatory T cells (Tregs) are critical in the prevention of IBD and Treg function was reported to be closely associated with ROS level, but it has been investigated only in lowered levels of ROS so far. In the present study, in order to clarify the relationship between ROS level and Treg function, and their role in the pathogenesis of IBD, we investigated mice with an elevated level of ROS due to deficiency of both glutathione peroxidase (GPx)-1 and catalase (Cat) for the susceptibility of DSS-induced colitis in association with Treg function. The results showed that DSS-induced colitis was attenuated and Tregs were hyperfunctional in GPx1−/− × Cat−/− mice. In vivo administration of N-acetylcysteine (NAC) aggravated DSS-induced colitis and decreased Treg function to the level comparable to WT mice. Attenuated Th17 cell differentiation from naïve CD4+ cells as well as impaired production of IL-6 and IL-17A by splenocytes upon stimulation suggested anti-inflammatory tendency of GPx1−/− × Cat−/− mice. Suppression of Stat3 activation in association with enhancement of indoleamine 2,3-dioxygenase and FoxP3 expression might be involved in the immunosuppressive mechanism of GPx1−/− × Cat−/− mice. Taken together, it is implied that ROS level is critical in the regulation of Treg function, and IBD may be attenuated in appropriately elevated levels of ROS.
Highlights
Reactive oxygen species (ROS) are highly reactive and interact with many bio-molecules
Flow cytometric analysis of the splenocytes stained with DCFDA after stimulation with PMA showed that the intracellular ROS level in the splenocytes from GPx12/2 6 Cat2/2 mice was higher than that from WT mice (Fig. 1A)
Among the T cells used in the suppression assay, intracellular ROS level was higher in CD4+CD25+ Tregs than in CD4+CD252 Teffs
Summary
Reactive oxygen species (ROS) are highly reactive and interact with many bio-molecules. At high concentrations, they are likely to destroy biological structures, promoting cellular damage and tissue destruction. Mice with lower level of ROS than WT mice due to defects in ROS-producing enzyme system, such as Ncf12/2 or Nox22/2, are more susceptible to autoimmune diseases, such as arthritis and encephalomyelitis [5,6,7]. Mice with higher level ROS than WT mice due to the defect in a ROS metabolizing enzyme, glutathione peroxidase-1 (GPx-1), are resistant to immune-mediated inflammatory diseases, such as allergen-induced airway inflammation and high fat diet-induced atherosclerosis [10,11]. Mice with higher level of ROS due to defect of a non-enzymatic cellular anti-oxidant, peroxiredoxin (Prx) II, are resistant to dextran sodium sulfate (DSS)-induced colitis [12]
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