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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-17
Interleukin-20
Interleukin-22
Interleukin-23
Interleukin-25
Interleukin-27
Interleukin-33

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

Malignancies rare following anti-TNF-a therapy; most patients discontinue biologics. A small number of patients developed a malignancy while receiving anti-tumor necrosis factor-alpha treatment for an autoimmune disease, and most who did discontinued treatment with biologic agents. Healio Rheumatology, 07/30/2015. (Also see Biologic Agents)

Interleukin-1{alpha}

Is Osteopontin (OPN) Involved in Cutaneous Fibroblast Activation? Its Hypothetical Role in Scleroderma Pathogenesis. OPN levels increase simultaneously with the increasing of alpha smooth muscle actin levels, therefore it is reasonable to hypothesize that OPN interferes in the pathogenesis of Systemic Sclerosis in the early stage of fibroblast differentiation process. International Journal of Immunopathology and Pharmacology, 01/29/2014.

Interleukin-6

Mechanistic insight into the norepinephrine (NE)–induced fibrosis in systemic sclerosis (SSc). These results suggest that cold exposure and/or emotional stress–induced NE might contribute to the skin fibrosis via potentiation of IL-6 production from fibroblasts in SSc. PMC, Sci Rep, 2016; 6: 34012.(Also see Fibroblasts)

IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia (FM) patients. These findings indicate that IL-6 and IL-8 are two of the most constant inflammatory mediators in FM and that their levels correlate significantly with the severity of symptoms. PubMed, J Neuroimmunol, 2016 Jan 15;290:22-5.

Interleukin-6 promoter haplotypes are associated with etanercept response in patients with rheumatoid arthritis. A genetically determined IL-6-dominated RA responds less well to anti-tumor necrosis factorore and work has to be done to provide reliable information regarding the functional aspects of these genetic polymorphisms. PubMed, Clin Rheumatol, 11/03/2015.

Relationship between interleukin-6 (IL-6) and cardiac involvement in systemic sclerosis (SSc). These results support the role of IL-6 in the development of cardiac disease in SSc patients. PubMed, Rheumatology. 03/27/2013. (Also see Cardiac Involvement)

Interleukin-8

Association of elevated α–defensin levels with interstitial pneumonia in patients with systemic sclerosis (SSc–ILD). Bronchoalveolar lavage fluid levels of defensins and IL-8 were higher in SSc–ILD than in healthy controls, and are associated with various clinical disease parameters. PubMed, Respir Res, 2015 Dec 10;16:148.

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, 2013 Feb;77(2):162-8.

Interleukin-12

Influence of tyrosine kinase 2 (TYK2) in systemic sclerosis (SSc) susceptibility: a new locus in the IL-12 pathway. The association of TYK2 with SSc and reinforcing the relevance of the IL-12 pathway in SSc pathophysiology is reported for the first time. PubMed, Ann Rheum Dis, 09/02/2015.

Interleukin-13

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. 2013 Nov-Dec;39(6):593-6.

Interleukin-17

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. 10/16/2015. (Also see Alopecia)

Interleukin (IL)-17A promotes functional activation of systemic sclerosis (SSc) patient-derived dermal vascular smooth muscle cells by extracellular regulated protein kinases signaling pathway. IL-17A-derived from patients with SSc might be promising therapeutic targets for the treatment of SSc-related vasculopathy. PubMed, Arthritis Res Ther, 2014 Dec 31;16(6):4223.

Interleukin-17 and interleukin-23: importance in the pathogenesis of lung impairment in patients with systemic sclerosis(SSc). While the relationship between Th17-associated cytokines and interstitial lung disease-SSc needs to be verified, the changes in concentrations of IL-17, IL-21 and IL-23 support the hypothesis that these cytokines may play a role in the pathogenesis of SSc. PubMed, Int J Rheum Dis, 2014 Jul;17(6):664-70.

Interleukin-20

Decreased Interleukin-20 Expression in Scleroderma (SSc) Skin Contributes to Cutaneous Fibrosis. IL-20 reduces basal collagen transcription via Fli-1 induction, while down-regulation of Smad3 and endoglin may cancel the effect of transforming growth factor in SSc fibroblasts. Arthritis Rheumatol, 2014 Jun; 66(6): 1636-1647.

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, 10/09/2015.

IL-22, not simply a Th17 cytokine. The production of IL-22 from various T-cell populations as well as protective versus pathogenic roles of IL-22 is discussed. PubMed, Immunol Rev, 2013 Mar;252(1):116-32.

Activated and resting regulatory T cell (Treg) exhaustion concurs with high levels of interleukin-22 expression in systemic sclerosis (SSc) lesions. SSc pathogenesis does not appear to be linked to IL-17-, but rather to IL-22-producing cells with skin-homing potential and a concomitant quantitative Treg defect. PubMed, Ann Rheum Dis, 2012 Jul;71(7):1227-34.

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, 06/25/2013.

Interleukin-25

A Jekyll and Hyde of cytokines: IL-25 both promotes and limits inflammatory diseases. The same signal responsible for promoting the type of immune responses that cause asthma and allergy can also limit the type of inflammation associated with debilitating diseases like inflammatory bowel disease, arthritis and multiple sclerosis. EurekAlert! [2006].

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, 09/28/2015.

University of Pennsylvania Researchers Identify Gatekeeper Involved in Chronic Inflammatory Diseases. Researchers found that IL-27 inhibits the immune system cells that are responsible for an array of inflammatory-related diseases, including encephalitis, arthritis, Crohns disease, lupus and even sepsis. University of Pennsylvania. [2006].

Interleukin-33

The IL-33 gene is related to increased susceptibility to systemic sclerosis (SSc). The aim of the present study was to detect the potential association of IL-33 gene polymorphisms on the susceptibility of SSc. Springer Link 01/07/2016.

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