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Crohn's disease (CD) is characterized by transmural inflammation that is most frequently located in the region of the terminal ileum. Although the physiopathological mechanisms of the disease are not yet well defined, the unregulated immune response is associated with high production of reactive oxygen species (ROS). These elements are associated with complex systems known as antioxidant defenses, whose function is ROS regulation, thereby preventing the harmful effects of these elements. However, the presence of an imbalance between ROS production and ROS elimination by antioxidants has been widely described and leads to oxidative stress. In this article, we describe the most significant findings on oxidative stress in the intestinal mucosa and peripheral blood.

© 2015 Elsevier Inc. Tissue effector cells of the monocyte lineage can differentiate into different cell types with specific cell function depending on their environment. The phenotype, developmental requirements, and functional mechanisms of immune protective macrophages that mediate the induction of transplantation tolerance remain elusive. Here, we demonstrate that costimulatory blockade favored accumulation of DC-SIGN-expressing macrophages that inhibited CD8+ Tcell immunity and promoted CD4+Foxp3+ Treg cell expansion in numbers. Mechanistically, that simultaneous DC-SIGN engagement by fucosylated ligands and TLR4 signaling was required for production of immunoregulatory IL-10 associated with prolonged allograft survival. Deletion of DC-SIGN-expressing macrophages invivo, interfering with their CSF1-dependent development, or preventing the DC-SIGN signaling pathway abrogated tolerance. Together, the results provide new insights into the tolerogenic effects of costimulatory blockade and identify DC-SIGN+ suppressive macrophages as crucial mediators of immunological tolerance with the concomitant therapeutic implications in the clinic., Ministerio de Educación y Ciencia SAF2010-15062, SAF2013-48834-R, and Fundación Mutua Madrileña

There is increasing interest in oxidative stress being a potential aetiological factor and/or a triggering factor in Crohn's disease, rather than a concomitant occurrence during the pathogenesis of the disease. Recent research has shown that the immune mononuclear cells of Crohn's disease patients are induced to produce hydrogen peroxide (H2O2). Similarly, the regulation of antioxidant enzymes during disease in these cells has been unravelled, showing that SOD (superoxide dismutase) activity and GPx (glutathione peroxidase) activity is increased during active disease and returns to normal in remission phases. However, catalase remains constantly inhibited which supports the idea that catalase is not a redox-sensitive enzyme, but a regulator of cellular processes. ROS (reactive oxygen species) can be produced under the stimulus of different cytokines such as TNFα (tumour necrosis factor α). It has been shown in different experimental models that they are also able to regulate apoptosis and other cellular processes. The status of oxidative stress elements in Crohn's disease and their possible implications in regulating cellular processes are reviewed in the present paper.

Background: An increase of oxidative stress (OxS) and a decrease of apoptosis have been reported as key factors in Crohn's disease (CD) pathogenesis. We have previously shown that OxS in CD depends on an increased production of H2O2 which detoxification is independent of catalase (CAT) enzyme because CAT showed permanently inhibited in CD patients1. CAT could be more implicated in regulating cellular processes, as apoptosis, than in detoxifying H2O2. Aims: To characterize the genetic expression of CAT and other OxS and apoptosis related genes in CD at beginning of the disease and when remission has been achieved. Methods: Blood samples were obtained from 18 healthy subjects (H), 20 patients at onset of CD and yet to begin any specific medication (active CD, aCD) and from 10 patients who achieved clinical, analytical and morphological remission (inactive CD, iCD). Patients were diagnosed according to Leonard-Jones criteria and disease activity was scored based on the Harvey-Bradshaw index, serological markers of inflammation (CRP, fibrinogen) and evaluation of morphological lesions (magnetic resonance enterography, colonoscopy or capsule endoscopy). PWMC were isolated by Histopaque sedimentation. Total RNA from leukocytes was extracted according to manufacturer's protocol (LeukoLOCKTM; Ambion). mRNA expression was measured by Sequenom's MassARRAY® quantitative gene expression analysis application. The genes analyzed were: CAT, SOD2, NOS2A, STAT1, NFKB1, PKCgamma, PKCzeta, PSKH1, PPID, ABCB1, ASK1, FASR, FASLG, TERT, IL-2, IL23R. Results: Genes differentially expressed in CD are summarized in the table. Specific upregulated genes during flair were SOD2, STAT1, and PSKH1, and down-regulated were FASL and ABCB1. In iCD, FASR and NFKB1 were up-regulated. The down-regulation of CAT gene expression was persistent. Conclusions: Up regulation of SOD2, STAT1 and PSKH1 only during a flare, indicates the relation between OxS and aCD. Down regulation of FASL and ABCB1 shows an apoptotic and multidrug resistance alteration at onset of the disease. Increased expression of FASR and NFKB1 in iCD could indicate that apoptosis are genetically affected in CD. Permanent inhibition of CAT activity in CD patients correlates to a persistent down regulation of the CAT-gene mRNA. The implications of CAT inhibition in regulating cellular processes such as apoptosis should be studied. 1) Beltran B, et al. Inflamm Bowel Dis. 2010 16:76-86.