Distinct Profiles of Effector Cytokines Mark the Different Phases of Crohn’s Disease

Abstract

ObjectiveCrohn’s Disease (CD)-associated inflammation is supposed to be driven by T helper (Th)1/Th17 cell-derived cytokines, even though there is evidence that the mucosal profile of cytokine may vary with the evolution of the disease. We aimed at comparing the pattern of effector cytokines in early and established lesions of CD.DesignMucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with (early lesions) or without post-operative recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (established lesions). Inflammatory cell infiltrate was examined by immunofluorescence and cytokine expression was analysed by real-time PCR, flow-cytometry and ELISA.ResultsBefore the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of T cells and macrophages, elevated levels of Th1-related cytokines and TNF-α and slightly increased IL-17A expression. Transition from this stage to endoscopic recurrence was marked by abundance of Th1 cytokines, marked increase in IL-17A, and induction of IL-6 and IL-23, two cytokines involved in the control of Th17 cell responses. In samples with established lesions, there was a mixed Th1/Th17 response with no TNF-α induction. Expression of IL-4 and IL-5 was up-regulated in both early and established lesions even though the fraction of IL-4-producing cells was lower than that of cells producing either interferon-γ or IL-17A.ConclusionsDistinct mucosal profiles of cytokines are produced during the different phases of CD. A better understanding of the cytokines temporally regulated in CD tissue could help optimize therapeutic interventions in CD.

Targeting T cells in Chronic Inflammatory Bowel Diseases

“…Hence, administration of drugs blocking Th17 cytokines could be not useful in the early stages of CD that are marked by an IL-12-associated Th1 cell response. In contrast, compounds inhibiting either Th1 or Th17 cytokines could be not sufficient to dampen the established phases of the disease, in which there is a predominant mixed Th1/Th17 cell response [88]. In conclusion, the data discussed in this article indicate that T cell-targeted therapy are useful in the management of IBD patients, even though further studies are needed to ascertain which patients could benefit from these treatments.…”

Giardia duodenalis Cathepsin B Proteases Degrade Intestinal Epithelial Interleukin-8 and Attenuate Interleukin-8-Induced Neutrophil Chemotaxis

“…Adapting from previous studies (52), we developed a novel method of modeling G. duodenalis interactions with human small intestinal tissues, whereby human small intestinal mucosal biopsy tissues collected from the terminal ileum of patients with CD in remission were coincubated with live G. duodenalis trophozoites. Ileal biopsy tissues from CD patients exhibit cytokine profiles that differ from those from individuals without CD (66,67) and therefore may have abnormal responses to proinflammatory cytokine stimulation. As a result, initial experiments sought to determine whether administration of IL-1␤ to these tissues resulted in enhanced secretion of CXCL8 ex vivo.…”

Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation

“…55 Additional cytokines contributing to impaired epithelial function have been identified, including the Th2-cytokines IL-4 and -13, IL-17, IL1b, and IL-6, and even mast cell released mediators such as histamine have been found to play a role. 56,57 However, it remains to be seen whether its pro-or anti-inflammatory effects on the intestinal epithelium will prevail. 58,59 Notably, these cytokines induce intestinal barrier defects in cultured epithelial cells and animal models that resemble those found in Crohn's disease patients, including TJ changes and epithelial apoptosis induction.…”