Articles That Use the Tag Name:

proinflammatory cytokine

Mechanisms of Autoimmune Liver Disease

Abstract: The immune system of the liver is characterized by a predominant innate component. Several innate immune cell populations have been implicated in the pathogenesis of immune-mediated hepatic diseases, which are frequently associated with systemic symptoms or with co-morbidities affecting other organ systems. Thus, next to tissue-specific factors, general tolerance mechanisms are affected in devastating hepatic disorders like primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), or primary biliary cirrhosis (PBC). The innate immune cell populations abundantly detected within the liver and endowed with potent immunomodulatory capacities include innate lymphoid cells (ILCs) and natural killer T (NKT) cells. While both ILCs and NKT cells can be activated by different cytokines and/or chemokines, NKT cells also respond to (glyco-) lipid antigens engaging their canonical, semi-invariant TCR. Once activated, ILCs and NKT cells release copious amounts of Th1, Th2, and/or Th17 cytokines that shape subsequent innate and adaptive immune responses. Those immunomodulatory features as well as the recently described antigen-presenting capacity of ILCs and/or the bi-directional functional role of NKT cells might not only underlie the pathogenic mechanisms in the respective disorders, but also provide promising targets for clinical intervention. We will discuss these novel aspects as well as the role of alarmin-like cytokines such as IL-33 in the context of ILC and NKT cell activation and the consequences for the induction and progress of hepatic tissue damage and fibrosis. ... Read more

MicroRNAs Regulate Immune System Via Multiple Targets

Abstract: MicroRNAs (miRNAs) represent the most abundant class of regulators of gene expression. Each miRNA may suppress multiple mRNA targets, while one mRNA can be targeted by many miRNAs for precise control of a wide range of cellular processes. The important role of miRNAs in the immune system is highlighted by the conditional Dicer knockout mouse, which exhibited profound aberrant development and function of immune cells. One particular miRNA, miR-155, is highly expressed and plays important role in lymphocytes. In this review we focused on the role of miRNA, especially miR-155, via their predicted and known mRNA targets in innate and adaptive immunity. Finally, we discussed the potential of miRNAs as novel targets for the diagnosis and therapy of immune system diseases. ... Read more

Advances in Pathogenesis and Treatment of ANCA-associated Vasculitis

Abstract: Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed to proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA) are sensitive and specific markers for their associated diseases, granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis) and microscopic polyangiitis (MPA), respectively. Clinical observations suggest but do not prove that ANCA are involved in the pathogenesis of GPA and MPA. In vivo and in vitro experimental data strongly suggest if not prove that MPO-ANCA underlie the pathological lesions seen in MPO-ANCA associated MPA. This is less clear for PR3-ANCA associated GPA in which, besides small-vessel vasculitis, granulomatous inflammation is apparent. Here, cellular immunity appears to play an additional role. Insight into the pathogenetic events involved in these diseases has resulted in new ways of treatment that target the specific pathways that underlie the development of the lesions. ... Read more

Bimodal Plasma Metabolomics Strategy Identifies Novel Inflammatory Metabolites in Inflammatory Bowel Diseases

Abstract: Introduction: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by variable phenotypes. Metabolites are signatures of biochemical activity that can reveal unknown pathogenic pathways. We employed untargeted mass spectrometry (MS) based metabolomics to identify novel inflammatory mechanisms in IBD and a targeted assay to quantify metabolites of the auto-immunomodulating kynurenine pathway (KP) in IBDs and health. Materials and Methods: Metabolome analysis of CD, UC, and control plasmas was performed on a Liquid Chromatography (LC)-MS/MS system. KP metabolites quinolinic acid (QA) and picolinic acid (PA) were quantified by gas chromatography/MS. Results: Nineteen UC, 25 CD, and 9 control plasmas were analyzed: 34 metabolites exhibited abundance profiles associated with CD by global metabolome analysis (P≤0.05, false discovery rate q≤0.01). Notably, inflammatory-implicated metabolites angiotensin IV (P=0.049, q<0.001), diphthamide (P=0.018, q<0.001), and GM3 gangliosides (P<0.001, q<0.001) were increased in CD. By targeted kynurenine metabolites assay, QA (73.53 ng/mL ± 23.40 SD) and combined kynurenine metabolites (CKM) were increased in CD (120.19 ± 39.71) compared to controls (QA  50.14 ± 15.04; P<0.01; CKM 92.73 ± 26.30; P<0.01). CD QA positively correlated with CDAI (r=0.85; P<0.01), CRP (r=0.46; P=0.01), and ESR (r=0.42; P=0.03), while CKMs correlated with CDAI (r=0.615; P<0.01) and CRP (r=0.615; P=0.02). Conclusions: Associations of angiotensin IV, diphthamide, and GM3 gangliosides with CD implicate novel pathways in activating a Th1/Th17 inflammatory profile. Increased QA concentrations in CD may indicate a defective auto-immunomodulation mechanism. ... Read more

Interplay Between microRNAs, Toll-like Receptors, and HIV-1: Potential Implications in HIV-1 Replication and Chronic Immune Activation

Abstract: MicroRNAs (miRNAs) are important cellular, small non-coding RNAs that regulate host gene expression and have well-characterized roles in inflammation and infectious diseases. It has become apparent as well that cellular miRNAs can play crucial roles in controlling HIV-1 infection and replication. Whether HIV-1 encodes and is able to express viral miRNAs in infected cells remains controversial. HIV-1 can manipulate the biogenesis of miRNAs as well as the expression profiles of cellular miRNAs. Toll-Like receptors (TLRs) are important pathogen recognition receptors that sense invading pathogens orchestrating innate and adaptive immune responses. Innate immune recognition of HIV-1 infection leads to activation of TLR7/8. Recent evidence has shown that certain miRNAs can also be recognized by TLR7/8 leading to immune activation. However, the potential TLR7/8-mediated recognition of HIV-1 encoded miRNAs and/or cellular miRNAs modulated in HIV-1 infected cells has not been experimentally explored. In this review, we summarize the current literature on HIV-1 infection and miRNAs. Furthermore, we underscore the need for future research on potential miRNA-induced activation of TLR7/8, which might contribute to the chronic immune activation observed in HIV-1 infected patients. ... Read more

Cholesterol Crystals Induce Inflammatory Cytokines Expression in a Human Retinal Pigment Epithelium Cell Line by Activating the NF-kappaB Pathway

Abstract: Purpose: To investigate the expression of inflammatory cytokines in ARPE-19 cells after stimulation with cholesterol crystals. Methods: APRE-19 cells were cultured, primed with IL-1α, and treated with cholesterol crystals under different concentrations. Inflammatory cytokines (mature-IL-1β, IL-6, and IL-8) in supernatant and inflammatory cytokines (pro-IL-1β, IL-18) in cell lysate were detected by western blot. The NF-κB pathway inhibitor BAY 11-7082 was used to determine the pathway of cytokine expression. Results: Cholesterol crystals did not induce the nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome, but did increase pro-IL-1β expression in ARPE-19 cells. Cholesterol crystals increased pro-IL-1β expression by activating the NF-κB pathway. Cholesterol crystal activation of the NF-κB pathway also leads to increased IL-6 and IL-8 expression. Conclusion: Cholesterol crystals can induce inflammatory cytokine expression in ARPE-19 cells by activating the NF-κB pathway. ... Read more

Novel Therapeutic Approaches for Celiac Disease

Abstract: Celiac disease (CD), which mainly affects the small intestine, is the only systemic autoimmune disorder with an identified environmental trigger which is dietary gluten. Lifelong adherence to a strict gluten free diet (GFD) is currently the only accepted treatment. CD is increasingly diagnosed and the GFD is known to be associated with a large treatment burden. Furthermore, a substantial number of CD patients show an incomplete clinical response to the GFD. These factors have led to demands for the development and testing of novel, non-dietary, therapeutic agents that are both safe and effective. CD pathogenesis is well elucidated which has greatly aided targeted drug development. Compounds currently being tested in phase II clinical trials include glutenase enzymes (to detoxify gluten) and a tight junction modulator (to reduce access of gluten peptides to lamina propria antigen presenting cells). Other promising approaches include inhibition of the transglutaminase 2 enzyme, blocking antigen presentation by HLA-DQ2 or HLA-DQ8, induction of tolerance, and modulation of the inflammatory response. It is hoped that non-dietary therapy for CD will become available in the coming years and can both reduce the burden of treatment of CD and help patients whose symptoms do not respond completely to the GFD. ... Read more

Advances in Mechanisms of Systemic Lupus Erythematosus

Abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease associated with hormonal, environmental, and genetic factors and linked to the tolerance breakdown of B and T cells to self-antigens. SLE is characterized by the presence in patient serum of autoantibodies raised against nuclear components. Association of these antibodies to self-antigens, complement factors, DNA, and particular proteins will form circulating immune complexes (CIC) which can deposit in several organs, causing tissue damage and clinical manifestations. Historically, SLE is considered as an adaptive immune system disorder. Over the past decade, advances in the understanding of SLE pathogenesis placed the innate immune system as a key player in perpetuating and amplifying this systemic disease. In this review, we summarize some recent key advances in understanding the SLE immune-pathogenesis with a particular focus on newly discovered key factors from the innate immune system and how they influence the pathogenic adaptive immune system: neutrophils and neutrophil extracellular traps (NETs), plasmacytoid dendritic cells (pDCs) and type I interferons, basophils and autoreactive IgE, monocytes/macrophages and the inflammasome. Recent advances on B and T cell involvement in the SLE pathogenesis mechanisms are also discussed. Although the disease is clinically, genetically, and immunologically heterogeneous between affected individuals, the latest discoveries are offering new promising therapeutic strategies. ... Read more

Treating IgA Nephropathy: Quid Novi?

Abstract: IgA nephropathy is a common autoimmune renal disease resulting in kidney failure for patients with significant proteinuria. The therapeutic options are limited including non-specific treatment to reduce proteinuria accomplished by renin-angiotensin blockade. Strategies to control intrarenal inflammation include the administration of fish oil and for severe disease the use of immunosuppressive agents such as cyclophosphamide, glucocorticosteroids, and mycophenolate mofetil. In light of the limited option, there is an unmet need for novel therapeutic intervention in patients with progressive disease. Herein, we review the evidence for existing treatment choices and explore new immunopharmacologic agents being investigated for IgA nephropathy. ... Read more

Novel Insight into the Role of Alpha-actinin-1 in Rheumatoid Arthritis

Abstract: The knowledge of rheumatoid arthritis (RA) pathology is rapidly advancing and becoming more and more complex, and a simple fact is that the major organ targeted by RA pathogenic factors is the synovium. It is well known that fibroblast-like synovial (FLS) cell is the major cell-type for constructing synovium. Following stimulation by pro-inflammatory cytokines, FLS cells are phenotypically changed to have the capability to proliferate abnormally. Recently we demonstrated that α-actinin-1 (ACTN1) gene is significantly increased in synovial tissues obtained from RA, as compared to osteoarthritis (OA). We therefore reviewed the literature about α-actinins (ACTNs) and we now propose that ACTN1 may function as a "terminal effector" of intracellular signalings initiated by tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) in RA. Future research on ACTN1 may help to improve the current therapeutic and diagnostic strategies of RA. ... Read more

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