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Causes of Scleroderma: Interleukins

Overview
Anti-TNF-a Therapies
Interleukin-1{alpha}
Interleukin-6
Interleukin-8
Interleukin-10
Interleukin-12
Interleukin-13
Interleukin-16
Interleukin-17
Interleukin-18
Interleukin-20
Interleukin-21
Interleukin-22
Interleukin-23
Interleukin-25
Interleukin-27
Interleukin-31
Interleukin-32
Interleukin-33
Interleukin-34

Overview

Photo of path in the autumnInterleukins are a vital part of the pathway that regulates inflammation in the body. There are many different types of interleukins.

Interleukins play a key role in the development or progression of inflammatory conditions.

Here we focus on the interleukins that are known to be involved with systemic sclerosis (scleroderma). (Also see What is Scleroderma? and Causes of Scleroderma)

Inflammation and Interleukins. Inflammation (Latin, inflammatio, to set on fire) is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a synonym for infection. Wikipedia.

Anti-TNF-a Therapies

Soluble TNF-R1, VEGF and other cytokines as markers of disease activity in systemic lupus erythematosus (SLE) and lupus nephritis (LN). These results indicate that for active LN, sTNF-R1 could be a useful serum cytokine marker, with potential for vascular endothelial growth factor in the urine. PubMed, Lupus, 2019 May 2:961203319845487. (Also see Diagnosis of Lupus)

Y-27632, a Rho–associated protein kinase inhibitor, inhibits systemic lupus erythematosus. The findings showed that the inhibition of rho-associated, coiled–coil–containing protein kinase 1(ROCK) was beneficial for the prevention of systemic lupus erythematosus, which possibly by suppressing NF-κB activation. PubMed, Biomed Pharmacother, 2017 Apr;88:359-366. (Also see Research on Systemic Lupus Erythematosus)

Interleukin-1{alpha}

Associations between Polymorphisms in the IL-1 Gene and the Risk of Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE): Evidence from a Meta-Analysis. This meta-analysis was performed to more robustly evaluate associations between polymorphisms in the IL-1 gene and the risk of RA/SLE. PubMed, Int Arch Allergy Immunol, 2020 Dec 7;1-9. (Also see Causes of Lupus and Causes of Rheumatoid Arthritis)

Cantargia Selects CAN10 as Development Project in Systemic Sclerosis and Myocarditis. Cantargia develops antibody-based pharmaceuticals against the interleukin 1 receptor accessory protein (IL1RAP) and the project will focus on unmet medical need in systemic sclerosis and myocarditis. PR Newswire, 12/05/2019.

The Roles of IL-1 Family Cytokines in the Pathogenesis of Systemic Sclerosis (SSc). Here, we aim to give a brief overview of IL-1 family cytokines and discuss their pivotal roles in the pathogenesis of SSc. PubMed, Front Immunol, 2019 Sep 13;10:2025.

Interleukin-6

Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis (SSc). The profound impact of IL-6R blockade on the activated fibroblast phenotype highlights the potential of IL-6 as a therapeutic target in SSc and other fibrotic diseases. PubMed, Ann Rheum Dis, 05/31/2018. (Also see Clinical Trials)

Elevated α-defensin levels in plasma and bronchoalveolar lavage fluid from patients with myositis-associated interstitial lung disease. Further studies are necessary to clarify whether human neutrophil peptides represent disease markers and play roles in disease pathogenesis. PubMed, BMC Pulm Med, 2018 Mar 12;18(1):44.

The combination of IL-6 and its soluble receptor is associated with the response of rheumatoid arthritis (RA) patients to tocilizumab. RA patients could be easily stratified prior to therapeutic intervention with two molecules related to the pathway blocked by tocilizumab. Seminars in Arthritis and Rheumatism, 11/03/2017. (Also see Treatments for Rheumatoid Arthritis)

The role and therapeutic targeting of IL-6 in rheumatoid arthritis (RA). The prospects for future applications, new therapeutic strategies of IL-6 targeting therapy and relevant issues with regard to the clinical management of IL-6 blockade in RA are discussed. PubMed, Expert Rev Clin Immunol, 2017 Jun;13(6):535-551. (Also see Causes of Rheumatoid Arthritis)

Interleukin-10

Interleukin-10 gene promoter and Nuclear factor-kB (NFKB)1 promoter insertion/deletion polymorphisms in systemic sclerosis (SSc). The association of the high-producing phenotype (GCC(+) /GCC(+) ) with increased risk for SSc was confirmed, but found no correlation with NFKB polymorphisms. PubMed, Scand J Immunol.

Interleukin-12

The Psoriasis-Protective TYK2 I684S Variant Impairs IL-12 Stimulated pSTAT4 Response in Skin-Homing CD4+ and CD8+ Memory T-cells These data establish the functional significance of the TYK2 I684S variant in psoriasis susceptibility. PubMed, Sci Rep, 2018 May 4;8(1):7043.

Interleukin-13

Association of interleukin 13 gene polymorphisms and plasma IL 13 level with risk of systemic lupus erythematosus (SLE). The concentration of IL-13 was significantly elevated in rs20541 CT/TT genotypes compared with CC genotype which suggests that rs20541 CT/TT genotypes may be a risk factor for SLE. PubMed, Cytokine, 10/07/2017. (Also see Causes of Lupus)

Transforming growth factor-ß increases interleukin-13 synthesis via GATA-3 transcription factor in T-lymphocytes from patients with systemic sclerosis (SSc). These results demonstrate that TGF-ß upregulates IL-13 synthesis through GATA-3 expression in the T lymphocytes of patients with SSc, confirming that the GATA-3 transcription factor can be regarded as a novel therapeutic target in patients with SSc. PubMed, Arthritis Res Ther. (Also see Molecular Defect)

Role of interleukin-13 in fibrosis, particularly systemic sclerosis. This review examines the role of IL-13 in driving fibrosis with a particular emphasis on systemic sclerosis as a prototypical fibrotic disease. PubMed, Biofactors.

Interleukin-16

IL-16 expression is increased in the skin and sera of patients with systemic sclerosis. The regional up-regulation of IL-16 in the skin is not only associated with skin sclerosis, but also with systemic IL-16 activation. PubMed, Rheumatology (Oxford), 08/03/2019. (Also see Skin Fibrosis)

Interleukin-17

The IL-23/IL-17 Pathway in Inflammatory Skin Diseases: From Bench to Bedside. We summarize the latest knowledge about the biology, signaling, and pathophysiological functions of the IL-23/IL-17 axis in inflammatory skin diseases. PubMed, Front Immunol, 2020 Nov 17;11:594735.

Interleukin-17A biomarker as a predictor for detection of early axial spondyloarthritis (SpA) changes in patients with psoriasis. Our study can imply that IL-17A is a valuable, useful and low–cost biomarker in detecting early axial SpA changes in asymptomatic and nonradiographic axial SpA psoriatic patients. PubMed, Int J Rheum Dis, 10/05/2020. (Also see Psoriasis and Psoriatic Arthritis)

The Role of the IL-23/IL-17 Pathway in the Pathogenesis of Spondyloarthritis In this review, we summarize the current knowledge of the pathomechanism by focusing on the IL-23/IL-17 pathway. PubMed, Int J Mol Sci, 2020 Sep 3;21(17):E6401. (Also see Psoriasis and Psoriatic Arthritis)

Serum concentrations of IL-17A, IL-17B, IL-17E and IL-17F in patients with systemic sclerosis (SSc). Increased synthesis of IL-17B, IL-17E and IL-17F appears to play a role in the pathogenesis of SSc, in contrast to IL-17A. PubMed, Arch Med Sci, 2019 May;15(3):706-712.

Interleukin-17 pathways in systemic sclerosis–associated fibrosis. There is multitude of evidence from across different tissues that interleukin-17 (IL-17) and its downstream pathways are strongly associated with the initiation and propagation of fibrosis. PubMed, Rheumatol Int, 05/09/2019. (Also see Skin Fibrosis)

Expression of interleukin-17 in primary Sjögren's syndrome (pSS) and the correlation with disease severity: A systematic review and meta–analysis. The expression of IL-17 is obviously increased in patients with pSS, especially among those without immunosuppressive treatment. PubMed, Scand J Immunol, 2018 Apr;87(4):e12649. (Also see Sjögren's Syndrome Research)

Serum 25–OH vitamin D level in treatment–naïve systemic lupus erythematosus (SLE) patients: Relation to disease activity, IL-23 and IL-17. Hypovitaminosis D contributes to ANA antibody production and is associated with high serum levels of IL-23 and IL-17 and may trigger the inflammatory process in SLE. Lupus, 2017 Aug;26(9):917-926. (Also see Research on Systemic Lupus Erythematosus)

Serum level of interleukin-17A in patients with alopecia areata (AA) and its relationship to age. It is possible that IL-17A plays a role in the pathogenesis of AA. Serum IL-17A may be influenced by patient age and age of onset of AA but does not seem to influence disease severity. PubMed, Int J Dermatol. (Also see Alopecia)

Interleukin-18

Investigation of genetically regulated gene expression and response to treatment in rheumatoid arthritis highlights an association between IL18RAP expression and treatment response. Our results suggest that IL18RAP expression is worthy of further investigation as a potential predictor of treatment response in rheumatoid arthritis. PubMed, Ann Rheum Dis, 2020 Nov;79(11):1446-1452. (Also see Treatments for Rheumatoid Arthritis)

Expression of interleukin-18 in muscle tissue of patients with polymyositis or dermatomyositis and effects of conventional immunosuppressive treatment. IL-18 is highly expressed in muscle tissue in the context of inflammatory myopathies and based on its plausible effector functions could provide a novel therapeutic target in future. PubMed, Rheumatology (Oxford), 08/08/2018. (Also see Treatments for Dermatomyositis and Polymyositis)

Interleukin-20

Interleukin-20 is triggered by toll–like receptor ligands (TLR) and associates with disease activity in patients with rheumatoid arthritis (RA). Our data showed that IL-20 is independently associated with RA disease activity and may be triggered by TLR ligands at local sites of inflammation. PubMed, Cytokine, 2017 Sep;97:187-192. (Also see Causes of Rheumatoid Arthritis)

Interleukin-21

Autoantibodies (AAbs) against interleukin-21 correlate with disease activity in patients with rheumatoid arthritis (RA). The levels of AAbs against IL-21 correlate with disease activity, which suggests that anti–IL-21 AAbs may play a role in the pathogenesis of RA. PubMed, Clin Rheumatol, 10/10/2017. (Also see Causes of Rheumatoid Arthritis)

Interleukin-22

IL-22 capacitates dermal fibroblast responses to tumour necrosis factor (TNF) in scleroderma. IL-22 capacitates fibroblast responses to TNF and promotes a proinflammatory fibroblast phenotype by favouring TNF-induced keratinocyte activation. PubMed, Ann Rheum Dis.

Interleukin-23

Pivotal Roles of T-Helper 17-Related Cytokines, IL-17, IL-22, and IL-23, in Inflammatory Diseases. Although some conflicting findings still need to be resolved, targeting Th17 cells and their related cytokines such as IL-17, IL-22, and IL-23 may be an effective therapeutic approach for chronic inflammation in the future. Clinical and Developmental Immunology.

Interleukin-25

Interleukin 25 (IL-25) expression in cholangiocarcinoma (CCA). Aberrant expression of IL-25 in CCA tissue was associated with tumor metastasis and poor prognosis, suggesting that IL-25 is a potential prognostic biomarker. PubMed, Mol Clin Oncol, 2020 Dec;13(6):84. (Also see Cancer)

Interleukin-27

IL-26 Plays Antimicrobial Role in Immune Response. Interleukin 17-producing helper T cells (Th17 cells) secrete copious amounts of interleukin 26 (IL-26) in patients with such autoimmune diseases as rheumatoid arthritis, psoriasis and inflammatory bowel disease. The Rheumatologist.

Interleukin-31

Interleukin-31 promotes pathogenic mechanisms underlying skin and lung fibrosis in scleroderma. IL-31/IL-31RA is confirmed as a candidate pro-fibrotic pathway, which may contribute to skin and lung fibrosis in a subset of scleroderma patients. PubMed, Rheumatology (Oxford), 05/04/2020.

Interleukin-32

Interleukin-32 in Systemic Sclerosis (SS), a Potential New Biomarker for Pulmonary Arterial Hypertension (PAH). Our study suggested that sera determination of IL-32 may be a promising approach to evaluate the presence of PAH in SSc patients. PubMed, Arthritis Res Ther, 2020 Jun 1;22(1):127. (Also see Pulmonary Hypertension Diagnosis)

Interleukin-33

IL-33/IL-31 Axis in Immune-Mediated and Allergic Diseases. This paper aims to give the readers a complete and updated review of IL-31 and IL-33 involvement among the most common autoimmune and allergic disorders. PubMed, Int J Mol Sci, 2019 Nov 22;20(23):5856

Interleukin-34

Interleukin-34 as a marker for subclinical proliferative lupus nephritis (LN). Serum IL-34 may be used as a surrogate marker for early renal affection in silent LN, especially the proliferative type. Sage Journals, Lupus, 04/01/2020. (Also see Symptoms and Complications of Lupus)

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