Role of Cytokines in Vitiligo: Pathogenesis and Possible Targets for Old and New Treatments

Vitiligo is a chronic autoimmune dermatosis of which the pathogenesis remains scarcely known. A wide variety of clinical studies have been proposed to investigate the immune mediators which have shown the most recurrency. However, such trials have produced controversial results. The aim of this review is to summarize the main factors involved in the pathogenesis of vitiligo, the latest findings regarding the cytokines involved and to evaluate the treatments based on the use of biological drugs in order to stop disease progression and achieve repigmentation. According to the results, the most recurrent studies dealt with inhibitors of IFN-gamma and TNF-alpha. It is possible that, given the great deal of cytokines involved in the lesion formation process of vitiligo, other biologics could be developed in the future to be used as adjuvants and/or to entirely replace the treatments that have proven to be unsatisfactory so far.

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VCAM-1 is a CS1 peptide-inhibitable adhesion molecule expressed by lymph node high endothelium

Journal of Cell Science ◽

10.1242/jcs.106.1.109 ◽

1993 ◽

Vol 106 (1) ◽

pp. 109-119 ◽

Cited By ~ 1

Author(s):

M.J. May ◽

G. Entwistle ◽

M.J. Humphries ◽

A. Ager

Keyword(s):

Lymph Node ◽

Cell Interaction ◽

Tnf Alpha ◽

Dependent Manner ◽

Ifn Gamma ◽

Lymphocyte Adhesion ◽

Peripheral Lymph ◽

Endothelial Surface ◽

Dose Dependent

Previous studies have shown that unactivated lymphocytes bind to CS1 peptide and that the adhesion of these cells to high endothelium is inhibited by CS1 peptide. These results suggest that lymphocyte binding occurs via recognition of the CS1-containing splice variant of fibronectin expressed on the high endothelial surface. We have now extended these studies by determining the role of the CS1 receptor, alpha 4 beta 1 (VLA-4) and the alternative VLA-4 ligand, VCAM-1 in a rat model of lymphocyte-high endothelial cell interaction. Anti-VLA-4 antibody, HP2/1, blocked lymphocyte adhesion to resting and IFN-gamma (interferon-gamma) pretreated cultured high endothelial cells (HEC) in a dose-dependent manner with maximal inhibition of 60%. HP2/1 completely blocked the adhesion of rat lymphocytes to immobilized CS1 peptide and to a recombinant soluble (rs) form of human VCAM-1. Lymphocyte binding to rsVCAM-1 was also completely blocked by CS1 peptide. Anti-rat VCAM-1 monoclonal antibody 5F10 inhibited adhesion to untreated and IFN-gamma-treated HEC equally and its effect at 50% inhibition was slightly less than that of HP2/1. These findings suggest that a CS1 peptide-inhibitable ligand expressed by high endothelium is VCAM-1. The majority of cultured HEC expressed significant levels of VCAM-1 under basal conditions, as did HEV in peripheral lymph nodes. VCAM-1 expression by HEC was upregulated by cytokine pretreatment and the effects were ordered: IFN-gamma > TNF-alpha > IL-1 beta. The results described here demonstrate that rat peripheral lymph node HEC express VCAM-1, its expression is upregulated by cytokines, in particular IFN-gamma, and it supports the adhesion of unactivated lymphocytes. They also suggest that the VLA-4/VCAM-1 adhesion pathway may operate during the constitutive migration of lymphocytes into lymphoid organs. Although the mechanism of CS1 peptide inhibition was not determined, these results show that VCAM-1 is a CS1 peptide-inhibitable ligand and therefore CS1, on its own, cannot be used as a specific indicator of fibronectin activity.

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Increased levels of circulating IL-10 in persons recovered from hepatitis C virus (HCV) infection compared with persons with active HCV infection

BMC Research Notes ◽

10.1186/s13104-020-05313-w ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Dorcas Ohui Owusu ◽

Richard Phillips ◽

Michael Owusu ◽

Fred Stephen Sarfo ◽

Margaret Frempong

Keyword(s):

Hepatitis C ◽

Spontaneous Recovery ◽

Predictive Marker ◽

Serum Levels ◽

Hcv Infection ◽

Tnf Alpha ◽

Hepatitis C Infection ◽

Ifn Gamma ◽

The Relationship

Abstract Objective Approximately 70% of all hepatitis C (HCV) infections develop chronic disease. Active or exacerbated chronic hepatitis C infection subsequently progress to liver disease. The role of T-cells secretions in achieving viral clearance is still not well understood. Thus, the current study was set to determine the relationship between the T cell cytokine profiles, biochemical parameters and persistent HCV infection or spontaneous recovery. Results Twenty-five percent (41/163) of the anti-HCV positive participants had recovered from HCV and had significantly higher concentration of IL-10 compared to those with active HCV infection (P < 0.012). Other circulating cytokines measured; IL-2, IFN gamma, TNF alpha, IL-5 and IL-17 were similar in both groups. Participants with active HCV infection had significantly higher aspartate transaminase (AST) (35 units) and alanine transaminase (46 units) compared to those in the recovered state (P < 0.001). Thus, serum levels of IL10 could be explored in larger prospective cohort study as a predictive marker of recovering from an active HCV infection.

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Role of TNF-Alpha, IFN-Gamma, and IL-10 in the Development of Pulmonary Tuberculosis

Pulmonary Medicine ◽

10.1155/2012/745483 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 96

Author(s):

Yone Vila Nova Cavalcanti ◽

Maria Carolina Accioly Brelaz ◽

Juliana Kelle de Andrade Lemoine Neves ◽

José Candido Ferraz ◽

Valéria Rêgo Alves Pereira

Keyword(s):

Immune Response ◽

Protective Immunity ◽

Critical Role ◽

Tnf Alpha ◽

Infection Site ◽

Ifn Gamma ◽

Major Function ◽

Reactive Nitrogen Intermediates ◽

Th1 And Th2 Responses

Host immune response againstMycobacterium tuberculosisis mediated by cellular immunity, in which cytokines and Th1 cells play a critical role. In the process of control of the infection by mycobacteria, TNF-alpha seems to have a primordial function. This cytokine acts in synergy with IFN-gamma, stimulating the production of reactive nitrogen intermediates (RNIs), thus mediating the tuberculostatic function of macrophages, and also stimulating the migration of immune cells to the infection site, contributing to granuloma formation, which controls the disease progression. IFN-gamma is the main cytokine involved in the immune response against mycobacteria, and its major function is the activation of macrophages, allowing them to exert its microbicidal role functions. Different from TNF-alpha and IFN-gamma, IL-10 is considered primarily an inhibitory cytokine, important to an adequate balance between inflammatory and immunopathologic responses. The increase in IL-10 levels seems to support the survival of mycobacteria in the host. Although there is not yet conclusive studies concerning a clear dichotomy between Th1 and Th2 responses, involving protective immunity and susceptibility to the disease, respectively, we can suggest that the knowledge about this responses based on the prevailing cytokine profile can help to elucidate the immune response related to the protection againstM. tuberculosis.

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Pathophysiology of Nasal Polyposis: The Role of Desmosomal Junctions

American Journal of Rhinology ◽

10.2500/ajr.2008.22.3235 ◽

2008 ◽

Vol 22 (6) ◽

pp. 589-597 ◽

Cited By ~ 34

Author(s):

Jodi D. Zuckerman ◽

Winston Y. Lee ◽

John M. DelGaudio ◽

Charles E. Moore ◽

Porfirio Nava ◽

...

Keyword(s):

Western Blot ◽

Nasal Polyps ◽

Nasal Polyposis ◽

Intercellular Junctions ◽

Tnf Alpha ◽

Protein Cleavage ◽

Ifn Gamma ◽

Inflammatory Conditions ◽

Junctional Proteins

Background Many mucosal inflammatory conditions are associated with alterations in epithelial intercellular junctions and barrier function; however, little is known about the role of intercellular junctions in inflammatory diseases of the upper airways. In this study, we examined nasal polyps for altered intercellular junctions and protein expression. Methods Biopsy specimens of nasal polyps and normal tissue were obtained intraoperatively from 11 patients and 6 controls. Tissue was analyzed for expression of intercellular junctional proteins by immunofluorescence. In parallel, cultured human bronchial epithelial (HBE) cells were treated with tumor necrosis factor (TNF) alpha, interferon (IFN) gamma, and IL-13 to simulate inflammatory conditions followed by assessment for changes in junctional proteins by immunofluorescence and Western blot. Results Of the intercellular junctional proteins analyzed, including proteins comprising tight and adherens junctions, the only alterations observed were in desmosomal proteins in nasal polyp epithelium compared with normal controls. Specifically, expression of desmosomal proteins DSG2 and DSG3 were significantly decreased in polyps versus controls (0.53 pixel/μm2 versus 1.09 pixel/μm2 [p = 0.009], and 0.29 pixel/μm2 versus 1.11 pixel/μm2 [p = 0.0078], respectively). In vitro experiments involving exposure of cultured HBE cells with inflammatory cytokines revealed that TNF-alpha treatment resulted in internalization and decreased expression of DSG2 by immunofluorescence and Western blotting. Treatment with IFN-gamma resulted in increased expression of DSG2 and evidence of protein cleavage by Western blot. IL-13 exposure resulted in down-regulation of DSG2 expression and evidence of protein cleavage. Conclusion These results indicate that nasal polyps express decreased levels of DSG2 and DSG3 components of desmosomal junctions. This is likely linked to the mucosal inflammatory response. Exposure of a respiratory cell line to Th1/Th2 cytokines results in similar expressional alterations in DSG2, suggesting protein internalization and cleavage. We speculate that weakened desmosomal junctions in nasal mucosa secondary to inflammatory cytokines may contribute to the formation of nasal polyposis.

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Antisense inhibition of 85-kDa cPLA2 blocks arachidonic acid release from airway epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1997.273.2.l331 ◽

1997 ◽

Vol 273 (2) ◽

pp. L331-L338 ◽

Cited By ~ 6

Author(s):

T. Wu ◽

S. J. Levine ◽

M. Cowan ◽

C. Logun ◽

C. W. Angus ◽

...

Keyword(s):

Arachidonic Acid ◽

Interleukin 1 ◽

Critical Role ◽

Airway Epithelial Cells ◽

Tnf Alpha ◽

Epithelial Cell Line ◽

Target Cells ◽

Ifn Gamma ◽

In Cells

Inflammatory cytokines play a critical role in the initiation and perpetuation of inflammation. Several cytokines are known to increase the production of arachidonic acid (AA) metabolites, which may mediate cytokine-induced acute and chronic inflammation. Although cytokines upregulate phospholipase A2 (PLA2) in several target cells, the contribution of individual PLA2 to cytokine-induced AA release and eicosanoid production remains unclear because of the existence of various forms of cellular PLA2. To examine the role of 85-kDa cytosolic PLA2 (cPLA2) in cytokine-induced AA release, a system was developed to inhibit the expression of cPLA2 in a human bronchial epithelial cell line (BEAS-2B cells) by antisense RNA. Cells stably expressing antisense cPLA2 exhibited decreased cPLA2 protein levels as well as decreased cPLA2 activity assayed in vitro. The effects of cytokines interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 alpha (IL-1 alpha) on the release of prelabeled [3H]AA were then tested in cells stably transfected with vector alone as well as cells transfected with cPLA2 antisense plasmid. IFN-gamma (300 U/ml), TNF-alpha (20 ng/ml), and IL-1 alpha (20 ng/ml) all induced a significantly increased release of prelabeled [3H]AA after 15 min to 2 h of treatment in control cells, and their effects were significantly reduced in cells transfected with cPLA2 antisense vector. These results demonstrate a critical role of cPLA2 in inflammatory cytokine-induced AA metabolism.

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PP008 Health Technology Assessment Analysis Of New Biological Drugs In Chronic Inflammatory Diseases

International Journal of Technology Assessment in Health Care ◽

10.1017/s0266462317002021 ◽

2017 ◽

Vol 33 (S1) ◽

pp. 70-71 ◽

Cited By ~ 1

Author(s):

Francesco Ferrara

Keyword(s):

Inflammatory Diseases ◽

Subcutaneous Administration ◽

Mechanisms Of Action ◽

Tnf Alpha ◽

Therapeutic Area ◽

Biological Drugs ◽

Chronic Inflammatory Diseases ◽

Innovative Therapies

INTRODUCTION:Innovative therapies with high cost are increasing in every therapeutic area, making it increasingly difficult the role of the pharmacist in trying to rationalize the economic resources to satisfy the needs of the entire population. The analysis of therapeutic appropriateness has a key role in the management of chronic inflammatory diseases where the biological drugs are used by patients for a long period of time. With increasing competition among companies and the advent of the first biosimilar drugs, the costs are declining and the duty of the Pharmacist is the supervision of treatments so that there is a good cost / effectiveness in an attempt to free resources and safeguard the survival of the Health Service National.METHODS:In the year 2015 up to September 2016, all patients were monitored in the departments of Rheumatology, Gastroenterology and Dermatology based on the type of disease, drugs, route of administration and dosages. We evaluated the previous non-biological treatments of first line, therapeutic switch between any drugs with different mechanisms of action, the analysis on the state of the disease, any therapeutic dosages not reported in Summary of Product Characteristics and the reasons that lead the doctors to deviate from guidelines.RESULTS:The treatments of 684 patients were analyzed: 409 in Rheumatology, 212 in Gastroenterology and 63 in Dermatology. The most frequently used drugs are those that have major use in clinical practice: Adalimumab, Etanercept and Infliximab (three anti-TNF alpha drugs). The first two, having a subcutaneous administration compared to intravenous administration, allow greater patient compliance and are therefore preferred to Infliximab. In Rheumatology the use of newer drugs with different mechanisms of action by inhibition of TNF alpha is not negligible and this is an indication of poor accuracy in the application of the guidelines.CONCLUSIONS:Biologicals are well tolerated and improve the quality of life of people with highly disabling diseases. The therapeutic appropriateness and adherence to guidelines are the only way to try to contain costs. The hope is that, in this new year 2017, new biosimilar drugs are approved that would make, at least for the naïve subjects, more sustainable management of these diseases.

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Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice.

Journal of Experimental Medicine ◽

10.1084/jem.179.1.305 ◽

1994 ◽

Vol 179 (1) ◽

pp. 305-310 ◽

Cited By ~ 391

Author(s):

H Ishida ◽

T Muchamuel ◽

S Sakaguchi ◽

S Andrade ◽

S Menon ◽

...

Keyword(s):

Lupus Erythematosus ◽

Interleukin 10 ◽

Protective Role ◽

Tnf Alpha ◽

Continuous Administration ◽

Necrosis Factor Alpha ◽

Immune Mediators ◽

Factor Alpha ◽

Necrosis Factor

We have previously shown that continuous administration of anti-interleukin 10 (anti-IL-10) antibodies (Abs) to BALB/c mice modifies endogenous levels of autoantibodies, tumor necrosis factor alpha (TNF-alpha), and interferon gamma, three immune mediators known to affect the development of autoimmunity in "lupus-prone" New Zealand black/white (NZB/W)F1 mice. To explore the consequences of IL-10 neutralization in NZB/W F1 mice, animals were injected two to three times per week from birth until 8-10 mo of age with anti-IL-10 Abs or with isotype control Abs. Anti-IL-10 treatment substantially delayed onset of autoimmunity in NZB/W F1 mice as monitored either by overall survival, or by development of proteinuria, glomerulonephritis, or autoantibodies. Survival at 9 mo was increased from 10 to 80% in anti-IL-10-treated mice relative to Ig isotype-treated controls. This protection against autoimmunity appeared to be due to an anti-IL-10-induced upregulation of endogenous TNF-alpha, since anti-IL-10-protected NZB/W F1 mice rapidly developed autoimmunity when neutralizing anti-TNF-alpha Abs were introduced at 30 wk along with the anti-IL-10 treatment. Consistent with the protective role of anti-IL-10 treatment in these experiments, continuous administration of IL-10 from 4 until 38 wk of age accelerated the onset of autoimmunity in NZB/W F1 mice. The same period of continuous IL-10 administration did not appear to be toxic to, or cause development of lupus-like autoimmunity in normal BALB/c mice. These data suggest that IL-10 antagonists may be beneficial in the treatment of human systemic lupus erythematosus.

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