Pro-inflammatory cytokine expression and the STAT1/3 pathway in canine chronic enteropathy and intestinal T-cell lymphoma.

The accumulation of intraepithelial lymphocytes (IELs) is a histopathological feature of canine chronic enteropathy (CE), and IELs are considered the cells of origin of intestinal T-cell lymphoma (ITCL). However, the pathogenic mechanism of IEL activation in CE remains unclear. This study hypothesized that the expression of proinflammatory cytokines, associated with cytotoxic T/NK-cell activation, is upregulated in CE and ITCL, and examined the expression of IFN-γ , IL-2 , IL-12p35, IL-12p40 , IL-15 , and IL-21 and the downstream signal transducers and activators of transcription (STAT) pathway in the duodenal mucosa of dogs without lesions ( n = 11; NC), with IEL ^- CE ( n = 19; CE without intraepithelial lymphocytosis), IEL ⁺ CE ( n = 29; CE with intraepithelial lymphocytosis), and with ITCL ( n = 60). Quantitative polymerase chain reaction (PCR) revealed that IFN-γ and IL-21 were higher in IEL ⁺ CE than in IEL ^- CE or NC. Western blot revealed upregulation of STAT1 and STAT3 in IEL ⁺ CE. Double-labeling immunohistochemistry revealed a positive correlation between the Ki67 index of CD3 ⁺ T-cells and IFN-γ expression levels. Immunohistochemistry revealed a higher ratio of p-STAT1-positive villi in IEL ⁺ CE and ITCL than IEL ^- CE and NC, which positively correlated with IFN-γ expression levels. Among the 60 ITCL cases, neoplastic lymphocytes were immunopositive for p-STAT1 in 28 cases and p-STAT3 in 29 cases. These results suggest that IFN-γ and IL-21 contribute to the pathogenesis of IEL ⁺ CE, and IFN-γ may be involved in T-cell activation and mucosal injury in CE. STAT1 and STAT3 activation in ITCL cells suggests a role for the upregulation of the STAT pathway in the pathogenesis of ITCL.
Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.