Calcitriol analog ZK191784 ameliorates acute and chronic dextran sodium sulfate-induced colitis by modulation of intestinal dendritic cell numbers and phenotype

AIM: To investigate the effects of ZK1916784, a low calcemic analog of calcitriol on intestinal inflammation. METHODS: Acute and chronic colitis was induced by dextran sodium sulfate (DSS) according to standard procedures. Mice were treated intraperitoneally with ZK1916784 or placebo and colonic inflammation was evaluated. Cytokine production by mesenterial lymph node (MLN) cells was measured by ELISA. Immunohistochemistry was performed to detect intestinal dendritic cells (DCs) within the colonic tissue, and the effect of the calcitriol analog on DCs was investigated. RESULTS: Treatment with ZK191784 resulted in significant amelioration of disease with a reduced histological score in acute and chronic intestinal inflammation. In animals with acute DSS colitis, down- regulation of colonic inflammation was associated with a dramatic reduction in the secretion of the proinflammatory cytokine interferon (IFN)-γ and a significant increase in intereleukin (IL)-10 by MLN cells. Similarly, in chronic colitis, IL-10 expression in colonic tissue increased 1.4-fold when mice were treated with ZK191784, whereas expression of the Th1-specific transcription factor T-beta decreased by 81.6%. Lower numbers of infiltrating activated CD11c+ DCs were found in the colon in ZK191784-treated mice with acute DSScolitis, and secretion of proinflammatory cytokines by primary mucosal DCs was inhibited in the presence of the calcitriol analog. CONCLUSION: The calcitriol analog ZK191784 demonstrated significant anti-inflammatory properties in experimental colitis that were at least partially mediated by the immunosuppressive effects of the derivate on mucosal DCs.

Loss of CD103^+ intestinal dendritic cells during colonic inflammation

AIM:To investigate possible differences in dendritic cells(DC)within intestinal tissue of mice before and after induction of colitis. METHODS:Mucosal DC derived from intestinal tissue,as well as from mesenteric lymph nodes and spleen,were analyzed by fluorescence activated cell sorting(FACS) analysis.Supernatants of these cells were analyzed for secretion of different pro-and anti-inflammatory cytokines. Immunohistochemistry and immunofluorescence were performed on cryosections of mucosal tissue derived from animals with colitis as well as from healthy mice. RESULTS:It was shown that DC derived from healthy intestinal lamina propria(LP)represented an immature phenotype as characterized by low-level expression of costimulatory cytokines.In contrast to DC from spleen and mesenteric lymph nodes(MLN)that secreted proinflammatory cytokines,LP-DC produced high levels of the anti-inflammatory cytokine IL-10.After induction of mu-rine colitis in a CD4 + CD62L + transfer model or in chronic Dextran sulfate sodium-colitis,a marked increase of activated CD80 + DC could be observed within the inflamed colonic tissue.Interestingly,in contrast to splenic DC,a significant population of DC within MLN and colonic LP expressed the mucosal integrin CD103 which was lost during colitis. CONCLUSION:The constitutive secretion of antiinflammatory cytokines by immature DC within the intestinal LP might regulate the homeostatic balance between mucosal immunity and tolerance.CD103 + DC could mediate this important function.

Smoking increases the risk of extraintestinal manifestations in Crohn's disease

AIM:To demonstrate a high prevalence of extraintestinal manifestations(EIMs)in a prospective populationbased cohort of inflammatory bowel disease(IBD)patients at first diagnosis as well as during the early course of the disease.METHODS:EIMs are common in patients with IBD.Data on the frequency of EIMs have mostly been assessed in patients from tertiary centers;however,data about the prevalence of EIMs at first diagnosis as well as factors influencing their incidence during the early course of disease from prospective population-based cohorts are scarce.We present data of patients of our population-based"Oberpfalz cohort"(Bavaria,Germany)from first diagnosis(up to 3 mo after first diagnosis)as well as during the early course of the disease.Possible risk factors were assessed by calculating the relative risk(RR)as well as using logistic regression analysis.RESULTS:In total,data of 257 newly diagnosed patients with IBD were evaluated[161 Crohn’s disease(CD),96 ulcerative colitis(UC)].Median duration of follow-up was 50 mo after first diagnosis.In 63.4%of all patients(n=163),an EIM was diagnosed at any point during the observation period.At first diagnosis,patients with CD had a significantly increased risk of an EIM[n=69(42.9%)]compared with UC patients[n=21(21.9%);P<0.001;RR=1.96;95%CI:1.30-2.98].Active smoking increased the risk of CD patients developing an EIM during the early course of the disease,but notably not of UC patients(P=0.046;RR=1.96;95%CI:1.01-3.79).In addition,using logistic regression analysis,the need for IBD-related surgery and a young age at first diagnosis were identified as risk factors for the development of an EIM in CD patients.No association with EIMs was found for the factors sex,localization of the disease and positive family history of IBD.In contrast,no key factors which increased the risk of development of an EIM could be identified in UC patients.CONCLUSION:We found a high prevalence of EIM in this cohort at first diagnosis and during the early course of the disease.In patients with CD,smoking,need for surgery and younger age at first diagnosis were risk factors for the development of an EIM.