IFN-γ mRNA expressions in patients who developed pouchitis were significantly higher than in patients without pouchitis (p=0.043). According to multivariate analysis, elevated IFN-γ mRNA levels were significantly associated with the onset of pouchitis.
The etiology of pouchitis is unknown, but so many different factors have been reported. Several studies reported an increased incidence of pouchitis in patients with extraintestinal manifestations19-23. Other studies reported that younger age23, shorter disease duration2, extent of disease2,23, more severe preoperative clinical course, steroid dependency27 and primary sclerosing cholangitis24-26 influenced the incidence of pouchitis. Some reported that even pre- and postoperative use of biologics28, steroid use before colectomy22,23, and postoperative use of nonsteroidal anti-inflammatory drugs21, have significantly correlated with pouchitis.
Idiopathic IBDs such as CD and UC occur in clinically immunocompetent individuals whose characteristic symptoms and signs arise from a robust, cytokine-driven inflammation of the gut29,30. Activation of T cells and monocytes/macrophages is regarded as an important factor in the pathogenesis of UC and CD, which is characterized by recurrent flare-ups of inflammation and a history of chronic enterocolitis12,31-34.
Traditionally, CD has been associated with a Th1 cytokine profile and UC has been associated with a Th2 cytokine profile 6,14,35-37. Recently, Th17 cells were introduced as a third and new lineage of Th cells14,38-40. Th17 cells produce IL-17A and to a lesser extent IL-17F, IL-22, IL-21, IL-26, TNF-α and IL-614,41,42. IL-23 is a newly discovered cytokine that has a role in the maintenance and/or expansion of Th17 cells41,43. Thus, IL-23/Th17 cells have been proposed to play a key role in intestinal inflammation, whereas IL-12/Th1 cells regulate systemic inflammation in IBD44,45. Increased IL-17 production by lamina propria CD4+ cells was induced by IL-23 stimulation that was significantly enhanced in UC. Consistently, IL-23 mRNA expression was positively correlated with IL-17 mRNA, but not with IFN-γ mRNA in UC46. Olsen et al., reported that the gene expression levels of IL-17A, IL-23 and IFN-γ correlated with the grade of inflammation in UC, and that IL-17A and IL-23 had a role in mediating inflammation in both forms of IBD14.
IFN-γ, a cytokine secreted by activated T cells and natural killer (NK) cells, promotes inflammation by activating macrophages and upregulating the expression of cell adhesion molecules47. Furthermore, increased IFN-γ production might be responsible for the tissue damage observed in pouchitis because IFN-γ sustains cytotoxic reactions48. Signal transducer and activator of transcription (STAT)1 is part of the signaling pathway of other cytokines/growth factor receptors as well as be a hallmark of IFN-γ receptor signal transduction 49-51. Previous studies investigating activation and expression of nuclear factor-kappa B (NF-κB) and members of the STAT family has positive correlation with the activation of cytokine transcription factors in IBD49-51. Although increased NF-κB activation was more predominant in CD than in UC, activation and expression of STAT1 were increased in UC compared with CD and normal controls51-53. A study investigating intracellular cytokine data reported that the pathophysiology of small-intestinal inflammation occurring after colectomy in patients with UC might be associated with a Th2 cytokine phenotype 54. Additionally, there was a significant increase in the number of IFN-γ producing mononuclear cells in patients with UC with pouchitis compared with UC patients without pouchitis55. Furthermore, there was a tendency towards increased levels of IFN-γ and STAT1 in patients with UC, even without clinical and endoscopic evidence of pouchitis 56. Of note, the normal pouch already indicated high levels of STAT1 expression and activation compared with normal preoperative ileum52.
There are some limitations in this cohort. First, this retrospective study included a limited number of patients with geographical reason from a single cohort. We were unable to detect the genuine number of the patients with pouchitis. Therefore, the finding needs to be validated in a larger prospective cohort. Second, the short follow-up time duration was insufficient to evaluate incidence of pouchitis. Nevertheless, our findings suggest that IFN-γ expression in the normal ileal mucosa at the time of colectomy may be an important factor in the pathophysiology of pouchitis.