Active ulcerative colitis is associated with downregulation of the TH1, TH2 and TH17 cytokine response and elevated IL-8 levels in mucosal biopsies

Abstract

Introduction Ulcerative colitis (UC) is a chronic infl ammatory condition of unconfi rmed aetiology. Microscopic examination of infl amed biopsies is characterised by an acute and chronic infl ammatory cell infi ltrate. There is confl icting evidence from experimental studies on the relative roles of TNFα, IL-8 and cytokines released by Th1, Th2 and Th17 lymphocytes in UC. This may be further complicated by interindividual variation in cytokine release due to genetic polymorphism. However, current therapy in infl ammatory bowel disease includes cytokine targeted interventions. The authors compared cytokine profi les of infl amed and non-infl amed mucosa in UC and age-sex matched controls. Methods Ethical approval was obtained. Patients were prospectively recruited from outpatients' clinics. Mucosal biopsies at fl exible sigmoidoscopy (FS) were taken from active UC patients within infl amed (active) and endoscopically normal proximal mucosa (internal control), and age-sex matched (external) controls undergoing FS. Quantitative cytokine analysis for IL-4, TNFα, IL-17A, IL-8 and IFNγ were carried out using commercially available assays on tissue homogenates prepared with protease inhibitors, corrected for total protein. Statistical comparison was by Wilcoxon signed rank pair analysis for non-parametric data. Results 69 active UC patients (54 paired normal/infl amed mucosa) and 69 controls were compared. No biologically significant differences were noted between normal tissue from colitis patients and external control mucosa. Cytokine measurements in infl amed mucosa compared with uninfl amed mucosa from the same patients demonstrated signifi cant reductions in IL-4 (p<0.005), IFNγ (p<0.002) and IL-17A. (p<0.002), whereas IL-8 (p<0.0005) was signifi cantly increased. Similarly, IFNγ was decreased (p<0.02) and IL-8 increased (p<0.0001) in infl amed mucosa compared with external control tissue; TNFα was not signifi cantly different in infl amed compared with control mucosa. Conclusion This fi ndings suggest that cytokine release within normal mucosa in UC patients is not signifi cantly different from matched controls; however, in infl amed mucosa, cytokines released by Th1, Th2 and Th17 lymphocytes are reduced and TNFα is unchanged. In contrast, IL-8 (a potent neutrophil chemoattractant) is elevated. These fi ndings suggest that the immunopathogenesis underlying the infl ammatory response in UC may be refl ective of an alternative to a Th1, Th2 and Th17 driven chronic infl ammatory system and may involve an IL-8 mediated leukocytic infi ltrate. Competing interests None.