102,420 research outputs found
Cytokine therapies in Crohn's disease: where are we now and where should we go?
No full textIn the gut of patients with Crohn's disease (CD), one of the major forms of inflammatory bowel diseases in humans, distinct subsets of T helper (Th) cells produce large amounts of cytokines, which are supposed to orchestrate the immuno-inflammatory process leading to the tissue damage. Indeed, cytokine blockers, including the three licensed anti-TNF-alpha and the neutralizing IL-12/p40 antibodies, have already been tested with success in CD. More than one third of patients do not respond to these treatments and response can wane with time. Moreover, blockade of such cytokines has been reported to associate with development of severe side effects and/or new immune-mediated pathologies. These findings and our better understanding of cytokine-associated effector pathways of tissue destruction suggest the necessity of novel cytokine-based therapies in CD
Interleukin-21 in chronic inflammatory diseases
No full textInterleukin-21 (IL-21), a cytokine produced by various subsets of activated CD4+ T cells, regulates multiple innate and adaptive immune responses. Indeed, IL-21 controls the proliferation and function of CD4+ and CD8+ T lymphocytes, drives the differentiation of B cells into memory cells and Ig-secreting plasma cells, enhances the activity of natural killer cells and negatively regulates the differentiation and activity of regulatory T cells. Moroever, IL-21 can stimulate nonimmune cells to synthesize various inflammatory molecules. Excessive production of IL-21 has been described in many human chronic inflammatory disorders and there is evidence that blockade of IL-21 helps attenuate detrimental responses in mouse models of immune-mediated diseases. In this article we briefly review data supporting the pathogenic role of IL-21 in immune-inflammatory pathologies and discuss the benefits and risks of IL-21 neutralization in patients with such diseases
Interleukin-21 in T cell-mediated diseases
No full textInterleukin-21 (IL-21), a cytokine produced by activated CD4+ T cells, activated natural killer T cells, and T follicular cells, has been reported to play a crucial role in the tissue-damaging T cell response in various organs, such as gut, skin, pancreas, and joints. This pathogenic effect is strictly linked to the ability of IL-21 to enhance the functional activities of multiple immune and non-immune cells. Consistently, studies from various laboratories have shown that blockade of IL-21 limits the progression of T cell-mediated inflammatory diseases in mice. Here we review the present knowledge on the expression and role of IL-21 in T cell-mediated pathologies
Th17 immune response in IBD: A new pathogenic mechanism
No full textAlthough traditionally associated with exaggerated Th1 or Th2 cell response, the gut inflammation occurring in patients with IBD is also characterized by production of cytokines made by a distinct lineage of T helper cells, termed Th17 cells. The discovery that this new inflammatory T-cell subset drives immune-mediated pathology and that the antigen-presenting cell-derived IL-23 is necessary for amplifying Th17 cell-associated inflammation has contributed to elucidate new pathways of intestinal tissue damage as well as to open new avenues for development of therapeutic strategies in IBD. In this review, we discuss the available data regarding the involvement of Th17 cells and their interplay with other mucosal cell types in the modulation of intestinal tissue inflammation. © 2008 European Crohn's and Colitis Organisation
Role of Smad7 in inflammatory bowel diseases
No full textCrohn's disease and ulcerative colitis, the major forms of inflammatory bowel diseases (IBD) in man, are complex diseases in which genetic and environmental factors interact to promote an excessive mucosal immune response directed against normal components of the bacterial microflora. There is also evidence that the pathologic process is due to defects in counter-regulatory mechanisms, such as those involving the immunosuppressive cytokine transforming growth factor (TGF)-β1. Indeed, studies in human IBD tissues and murine models of colitis have documented a disruption of TGF-β1 signalling marked by a block in the phosphorylation of Smad3, a signalling molecule associated with the activated TGF-β receptor, due to up-regulation of Smad7, an intracellular inhibitor of Smad3 phosphorylation. Knock-down of Smad7 with a specific antisense oligonucleotide restores TGF-β1/Smad3 signalling, thus resulting in a marked suppression of inflammatory cytokine production and attenuation of murine colitis. These findings together with the demonstration that Smad7 antisense oligonucleotide is not toxic when administered in mice have paved the way for the development of a Smad7 antisense oligonucleotide-based pharmaceutical compound that is now ready to enter the clinics. In this article we review the available data supporting the pathogenic role of Smad7 in IBD and discuss whether and how Smad7 antisense therapy could help dampen the ongoing inflammation in IBD
Molecular Targets of TRAIL-Sensitizing Agents in Colorectal Cancer
No full textTumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL), a member of the TNF superfamily, interacts with its functional death receptors (DRs) and induces apoptosis in a wide range of cancer cell types. Therefore, TRAIL has been considered as an attractive agent for cancer therapy. However, many cancers are resistant to TRAIL-based therapies mainly due to the reduced expression of DRs and/or up-regulation of TRAIL pathway-related anti-apoptotic proteins. Compounds that revert such defects restore the sensitivity of cancer cells to TRAIL, suggesting that combined therapies could help manage neoplastic patients. In this article, we will focus on the TRAIL-sensitizing effects of natural products and synthetic compounds in colorectal cancer (CRC) cells and discuss the molecular mechanisms by which such agents enhance the response of CRC cells to TRAIL
Investigational cytokine-targeted therapies for ulcerative colitis
No full textIntroduction: Up to one-third of patients with ulcerative colitis (UC) do not respond to standard medications, including mesalamine, steroids and thiopurines. The recognition that UC-related pathological process is the result of an altered balance between inflammatory and counter-regulatory signals, mostly mediated by cytokines, has led to the development of novel compounds, which are now ready to move into clinical practice. This article summarizes the recent data on the development and use of compounds either inhibiting inflammatory cytokines or enhancing the activity of counter-regulatory cytokines in patients with UC and murine models of UC. Areas covered: A PubMed search was performed using the following keywords: 'ulcerative colitis', 'therapy', 'treatment' and 'cytokine'. In addition, ongoing clinical trials were checked and compounds were searched on the website of pharmaceutical companies. Expert opinion: Several investigational cytokine-based therapies have provided promising results in attenuating clinical activity in patients with UC and mice with experimental colitis. However, clinical and immunological heterogeneity of UC patients, therapy-related side effects and redundant biological functions of cytokines represent potential pitfalls and should be considered in optimizing therapeutic strategies
Proteinase activated-receptors-associated signaling in the control of gastric cancer
No full textGastric cancer (GC) is the fourth most common cancer in the world and the second cause of cancer-related death. Gastric carcinogenesis is a multifactorial process, in which environmental and genetic factors interact to activate multiple intracellular signals thus leading to uncontrolled growth and survival of GC cells. One such a pathway is regulated by proteinase activated-receptors (PARs), seven transmembrane-spanning domain G protein-coupled receptors, which comprise four receptors (i.e. , PAR-1, PAR-2, PAR-3, and PAR-4) activated by various proteases. Both PAR-1 and PAR-2 are over-expressed on GC cells and their activation triggers and/or amplifies intracellular pathways, which sustain gastric carcinogenesis. There is also evidence that expression of either PAR-1 or PAR-2 correlates with depth of wall invasion and metastatic dissemination and inversely with the overall survival of patients. Consistently, data emerging from experimental models of GC suggest that both these receptors can be important targets for therapeutic interventions in GC patients. In contrast, PAR-4 levels are down-regulated in GC and correlate inversely with the aggressiveness of GC, thus suggesting a negative role of this receptor in the control of GC. In this article we review the available data on the expression and role of PARs in GC and discuss whether manipulation of PAR-driven signals may be useful for interfering with GC cell behavior
Interleukin-21 as a new therapeutic target for immune-mediated diseases
No full textCytokines have a decisive role in initiating and shaping pathologic responses in patients with various immune-inflammatory diseases. Recent studies indicate that interleukin (IL)-21, a cytokine produced mostly by activated CD4+ T cells, participates in the tissue damage in various tissues, owing to its ability to regulate the function of immune and non-immune cells. For instance, IL-21 controls the differentiation and functional activity of T cells, B cells and NK cells, limits the differentiation of inducible regulatory T cells (Tregs), and makes T cells resistant to the Treg-mediated immunesuppression. It also stimulates epithelial cells and fibroblasts to produce inflammatory mediators. Here, we focus on data supporting the pathogenic role of IL-21 in human inflammatory diseases and discuss pre-clinical studies that suggest that neutralization of IL-21 in vivo could be a new biological therapy to combat immune-mediated pathologies, such as inflammatory bowel diseases, diabetes, rheumatoid arthritis and systemic lupus erythematosus
- …
