Defective expression of scavenger receptors in celiac disease mucosa.

Celiac disease (CD) is a gluten sensitive enteropathy characterized by a marked infiltration of the mucosa with immune cells, over-production of inflammatory cytokines and epithelial cell damage. The factors/mechanisms that sustain and amplify the ongoing mucosal inflammation in CD are not however fully understood. Here, we have examined whether in CD there is a defective clearance of apoptotic cells/bodies, a phenomenon that helps promote tolerogenic signals thus liming pathogenic responses.

Plasma cells in the mucosa of patients with inflammatory bowel disease produce granzyme B and possess cytotoxic activities.

In both Crohn's disease (CD) and ulcerative colitis (UC), the gut is massively infiltrated with B cells and plasma cells, but the role of these cell types in the pathogenesis of gut tissue damage remains largely unknown. Human B cells express granzyme B (GrB) when cultured with IL-21, a cytokine overproduced in CD and UC mucosa. We therefore examined whether mucosal B cells express GrB and have cytotoxic activity in inflammatory bowel disease (IBD).

Preclinical studies of a specific PPARγ modulator in the control of skin inflammation.

Peroxisome proliferator-activated receptor γ (PPARγ) antagonizes inflammatory signals by interfering with NF-κB nuclear translocation. Consistently, PPARγ agonists have been proposed in various inflammatory skin disorders, but their wide use has been limited by severe side effects. Classes of compounds with specific PPARγ agonism have been designed to selectively target inflammatory pathways.

Lesional accumulation of CD163-expressing cells in the gut of patients with inflammatory bowel disease.

Monocytes/macrophages displaying different markers of activation/differentiation infiltrate the inflamed gut of patients with inflammatory bowel diseases (IBD), but the role that each monocyte/macrophage subpopulation plays in the pathogenesis of IBD is not fully understood. The hemoglobin scavenger receptor CD163, a specific marker of monocytes/macrophages, has been associated with either anti-inflammatory or inflammatory functions of macrophages in several pathologies. In this study we examined the tissue distribution and function of CD163-expressing monocytes/macrophages in IBD.

IL-25 prevents and cures fulminant hepatitis in mice through a myeloid-derived suppressor cell-dependent mechanism.

Unlabelled: Fulminant hepatitis (FH) is a disease characterized by massive destruction of hepatocytes with severe impairment of liver function. The pathogenesis of FH is not fully understood, but hyperactivity of T cells and macrophages with excessive production of cytokines are important hallmarks of the condition. In this study, we investigated the role of interleukin (IL)-25 in FH.

Interleukin-21 in chronic inflammatory diseases.

Interleukin-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.

High expression of the "A Disintegrin And Metalloprotease" 19 (ADAM19), a sheddase for TNF-α in the mucosa of patients with inflammatory bowel diseases.

Background: Tumor necrosis factor α (TNF-α) plays a major role in the tissue-damaging immune response in inflammatory bowel diseases (IBDs). The tissue concentration of TNF-α is related to the activity of "A Disintegrin And Metalloprotease" (ADAMs), enzymes that process membrane-bound TNF-α and liberate the TNF-α trimer into the extracellular environment. Although IBD-related inflammation is associated with high ADAM17 levels, the contribution of other members of the ADAMs family is not known.

Distinct profiles of effector cytokines mark the different phases of Crohn's disease.

Objective: Crohn'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.

Design: Mucosal 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).

Tissue inhibitor of metalloproteinase-3 regulates inflammation in human and mouse intestine.

Background & Aims: Tissue inhibitor of metalloproteinases (TIMP)-3 is an inhibitor of matrix metalloproteinases, which regulates tissue inflammation, damage, and repair. We investigated the role of TIMP-3 in intestinal inflammation in human beings and mice.

Methods: We used real-time polymerase chain reaction and flow cytometry to measure levels of TIMP-3 in intestine samples from patients with Crohn's disease (CD) and those without (controls).

Interleukin-21 in immune and allergic diseases.

Interleukin-21 (IL-21), a cytokine produced by various subsets of activated CD4+ T cells, plays a major role in the control of innate and adaptive immune responses. IL-21 biological activity is mediated by binding of the cytokine to a heterodimeric receptor, composed of a specific subunit, termed IL-21 receptor (IL-21R), and the common γ-chain, that is shared with IL-2, IL-4, IL-7, IL-9 and IL-15 receptors. IL-21 stimulates the proliferation of CD4+ and CD8+ T lymphocytes and regulates the profile of cytokines secreted by these cells, drives the differentiation of B cells into memory cells and Ig-secreting plasma cells, and enhances the activity of natural killer cells.

What's the next best cytokine target in IBD?

In the gut of patients with inflammatory bowel disease (IBD), immune and nonimmune cells produce large amounts of cytokines that drive the inflammatory process leading to the tissue damage. Cytokine blockers, such as anti-tumor necrosis factor alpha (TNF-α), have been used with some success in IBD. However, not all patients respond, and the therapeutic effects wane with time, demonstrating the need for more effective and long-lasting antiinflammatory strategies.

Smad7 expression in T cells prevents colitis-associated cancer.

Patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer due to chronic inflammation. In IBD, chronic inflammation relies upon a TGFβ signaling blockade, but its precise mechanistic relationship to colitis-associated colorectal cancer (CAC) remains unclear. In this study, we investigated the role of the TGFβ signaling inhibitor Smad7 in CAC pathogenesis.

Involvement of interleukin-21 in the regulation of colitis-associated colon cancer.

Chronic inflammation is a major driving force in the development of cancer in many tissues, but the array of factors involved in this neoplastic transformation are not well understood. We have investigated the role of interleukin (IL)-21 in colitis-associated colon cancer (CAC), as this cytokine is overexpressed in the gut mucosa of patients with ulcerative colitis (UC), a chronic inflammatory disease associated with colon cancer. IL-21 was increased in the gut of patients with UC-associated colon cancer, and in mice with CAC induced by azoxymethane (AOM) and dextran sulfate sodium (DSS).

Disruption of inflammatory signals by cytokine-targeted therapies for inflammatory bowel diseases.

Gut inflammation occurring in patients with inflammatory bowel diseases (IBD) is associated with an excessive immune response that is directed against constituents of the normal bacterial flora and results in the production of large amounts of inflammatory cytokines. Anti-cytokine compounds, such as the neutralizing TNF antibodies, have been employed with clinical success in patients with IBD. However, nearly half of IBD patients are refractory to such treatments, response can wane with time, and anti-TNF treatment can associate with severe side effects and/or development/exacerbation of extra-intestinal immune-mediated pathologies.

Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract.

Background & Aims: The pathogenesis of inflammatory bowel disease (IBD) is believed to involve an altered balance between effector and regulatory T cells. Aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor that mediates the toxicity of dioxins, controls T-cell responses. We investigated the role of AhR in inflammation and pathogenesis of IBD in humans and mouse models.

IL-21 promotes skin recruitment of CD4(+) cells and drives IFN-γ-dependent epidermal hyperplasia.

Psoriasis is a chronic inflammatory disorder of the skin characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis. T cell-derived cytokines, such as IFN-γ and IL-17A, play a major role in the psoriasis-associated epidermal hyperplasia, even though factors/mechanisms that regulate the production of these cytokines are not fully understood. We have recently shown that IL-21 is synthesized in excess in psoriatic skin lesions and causes epidermal hyperplasia when injected intradermally in mice.

Targeting interleukin-21 in inflammatory diseases.

Introduction: IL-21, a new member of the type 1 cytokine superfamily, is produced by various subsets of CD4(+) T cells and binds to a composite receptor that consists of a specific receptor, termed IL-21 receptor and the common γ-chain subunit. Initially considered to be a critical regulator of T and B cell function, IL-21 is now known to regulate the activity of many other cell types, including both immune and non-immune cells.

Areas Covered: In this review, we discuss the biological features of IL-21 and summarize recent advances in the pathogenic role of IL-21 in chronic inflammatory diseases.

Targeting IL-23 and Th17-cytokines in inflammatory bowel diseases.

Over the last 15 years, the use of various biological therapies has largely improved the way we manage patients with Inflammatory Bowel Diseases (IBDs). Blockade of cytokine synthesis and/or activity is at the forefront of this new era with the success of inhibitors of tumor necrosis factor (TNF)-α. These therapies are however not effective in all IBD patients and efficacy may wane.

IL-21 in the pathogenesis and treatment of skin diseases.

Interleukin-21 (IL-21) is a potent immunomodulatory cytokine, with pleiotropic effects on both innate and adaptive immune responses. These actions include positive effects, such as enhanced proliferation of lymphoid cells, increased cytotoxicity of CD8(+) T cells and natural killer cells, and differentiation of B cells into plasma cells. IL-21 is also produced by Th17 cells and is a critical regulator of Th17 development.

Interleukin-25 fails to activate STAT6 and induce alternatively activated macrophages.

Interleukin-25 (IL-25), a T helper type 2 (Th2) -related factor, inhibits the production of inflammatory cytokines by monocytes/macrophages. Since Th2 cytokines antagonize classically activated monocytes/macrophages by inducing alternatively activated macrophages (AAMs), we here assessed the effect of IL-25 on the alternative activation of human monocytes/macrophages. The interleukins IL-25, IL-4 and IL-13 were effective in reducing the expression of inflammatory chemokines in monocytes.

Interleukin-21 triggers effector cell responses in the gut.

In the gut of patients with Crohn's disease and patients with ulcerative colitis, the major forms of inflammatory bowel diseases (IBD) in humans, the tissue-damaging immune response is mediated by an active cross-talk between immune and non-immune cells. Accumulating evidence indicates also that cytokines produced by these cells play a major role in initiating and shaping this pathologic process. One such cytokine seems to be interleukin (IL)-21, a member of the common gamma-chain-receptor family.

Interleukin-21: a new mediator of inflammation in systemic lupus erythematosus.

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder characterized by excessive production of a variety of autoantibodies and a wide range of clinical manifestations. Pathogenesis of SLE is complex and not fully understood. There is however evidence that B and T cells are critical to the development of disease, and that T cell-derived cytokines are involved in the SLE-associated inflammatory response.

IL-23/IL-17 axis in IBD.

Gut inflammation occurring in patients with Crohn's disease and patients with ulcerative colitis has been traditionally associated with an exaggerated Th1 or Th2 cell response, respectively. However, recent studies have shown that in both inflammatory bowel diseases (IBD) there is also enhanced synthesis of cytokines made by a distinct subset of T helper cells, termed Th17 cells. The discovery that this new T-cell subset drives immune-mediated pathology in the gut, and that interleukin (IL)-23 amplifies Th17 cell responses and gut inflammation, has contributed to elucidate new pathways of tissue damage as well as to open new avenues for development of therapeutic strategies in IBD.

Interferon-gamma-expressing cells are a major source of interleukin-21 in inflammatory bowel diseases.

Background: We previously demonstrated that in inflammatory bowel disease (IBD) there is enhanced production of interleukin (IL)-21, a cytokine that activates multiple pathways that sustain mucosal inflammation. However, the phenotype of IL-21-producing cells in IBD, and the cytokine(s) they coproduce, is not known. We here characterized the cell source of IL-21 and determined which factors regulate IL-21 in the human gut.