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Review the Significance of Interleukin-6

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Review the Significance of Interleukin-6 Review The significance of interleukin-6 and C-reactive protein in systemic sclerosis: a systematic literature review C. Muangchan1,2,3, J.E. Pope2 1Research Fellow, Rheumatology; ABSTRACT Introduction 2Schulich School of Medicine & Dentistry, Objectives. Interleukin-6 (IL-6) may Systemic sclerosis (SSc) or scleroder- Western University of Canada (formerly play a role in the pathogenesis of SSc. ma is a systemic autoimmune rheumat- University of Western Ontario), St Joseph C-reactive protein (CRP), an acute ic disease characterised by autoimmun- Health Care, London, ON; 3Division of Rheumatology, Department of phase reactant induced by IL-6, may be ity; fibrosis and dysfunction in vascular Medicine, Faculty of Medicine, Mahidol a prognostic marker in SSc. The goal of regulatory mechanisms highlighted by University, Siriraj Hospital, Bangkok, this systematic review was to address vasculopathy of microcirculation (1). Thailand. the significance and clinical applica- SSc has increased extracellular matrix Chayawee Muangchan, Research Fellow tion of IL-6 and CRP in systemic scle- protein deposition due to increased fi- Janet Elizabeth Pope, MD rosis (SSc). broblast biosynthetic activity (2). SSc is Please address correspondence Methods. A literature search was con- rare and has a female predisposition (3, and reprint requests to: ducted to identify English-language 4). It is classified into diffuse cutane- Dr Janet Pope, original articles within PubMed, Sco- ous SSc (dcSSc) and limited cutaneous St. Joseph’s Health Care, London, SSc (lcSSc) subsets according to extent 268 Grosvenor St., pus, and Medline database from incep- London N6A 4V2, ON, Canada. tion to May 30, 2013 using keywords of cutaneous involvement (5). Patients E-mail: [email protected] “systemic sclerosis or scleroderma and with dcSSc have more skin involve- Received on January 26, 2013; accepted C-reactive protein or interleukin-6”. ment and worse survival rates than lcSSc (6-9). in revised form on May 6, 2013. Results. The search resulted in 156 The pathogenesis of SSc is still obscure Clin Exp Rheumatol 2013; 31 (Suppl. 76): relevant articles. Some single nucleo- as there are no true animal models, but S122-S134. tide polymorphisms and gene-gene immune activation is present with com- © Copyright CLINICAL AND interactions affect SSc predisposition, plex cytokines and protein interactions. EXPERIMENTAL RHEUMATOLOGY 2013. manifestation and expression of IL-6. T helper 1 lymphocyte (Th1) cytokines Studies in animal models show IL-6 Key words: scleroderma, systemic e.g. interferon-γ (IFN-γ), tumour ne- and IL-6 trans-signalling are involved sclerosis, interleukin 6, C-reactive crosis factor-α (TNF-α), interleukin-1α in SSc disease development. Derange- protein, systematic review (IL-1α), IL-2 and Th17 cytokines e.g. ments of T and B cells function regulate IL-17, IL-21, IL-23, IL-22 promote in- IL-6 in SSc pathogenesis. Fibroblasts, flammation in SSc, while Th2 cytokines T/B cells, monocytes, macrophages, e.g. IL-4, IL-13, IL-6, IL-10 contribute dendritic cells and endothelial cells tissue fibrosis (10). Interestingly, IL-6 participate in IL-6 expression and in- has a pro-inflammatory function via teract with each other resulting in tis- Th17 differentiation in the presence of sue sclerosis. Up-regulation of serum transforming growth factor-β (TGF-β)/ IL-6 and CRP levels are evident in SSc IL-21 and inhibition of T regulatory patients and associated with disease lymphocyte (Treg) differentiation as activity, severity, disability, worse out- well as fibrogenesis via stimulation of come and reduced survival. Targeted collagen production and inhibition of IL-6 therapy in SSc has occurred in collagenase synthesis (10). small cases series and within a multi- IL-6 also participates in the pathogen- site trial that is under way. esis of a variety of chronic inflammato- Conclusions: Studies show IL-6 and ry disease such as rheumatoid arthritis CRP are important in SSc both in (RA) (11) especially for systemic bone Competing interests: J. Pope received a pathogenesis and clinical manifesta- loss and structural bone damage (12). grant from the Canadian Arthritis Network to study IL-6 in SSc and is a site PI for the tions and may be useful indicators of Treatment with a humanised anti-inter- Genentech Tocilizumab in SSc trials; disease activity, severity, and poor leukin-6 receptor monoclonal antibody C. Muangchan has declared no competing prognosis. IL-6 could be a relevant corrects Th17/Treg cell imbalance (13) interests. treatment target in SSc. and demonstrate efficacy and safety in S-122 IL-6 and CRP in SSc / C. Muangchan & J.E. Pope REVIEW associated with SSc. The TT genotype of TBX21 rs 11650354 SNP variant has a recessive pattern for SSc suscep- tibility, while the A allele of STAT4 rs 11889341 has a dominant pattern. SSc patients carrying the CC genotype of TBX21 rs 11650354 have higher pro- inflammatory cytokines - interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) levels; and those with the TT genotype have elevated IL-2, IL-5, IL- 4, and IL-13 levels (21). There are also significant gene-gene interactions for SNPs in cytokine genes for SSc subset susceptibility such as IL-2 G-330T, IL-6 C-174G, and IFN-γ AUTR5644T SNPs in lcSSc susceptibility and IL-1R (IL- 1 receptor) Cpst1970T, IL-6 Ant565G, and IL-10 C-819T SNPs in dcSSc sus- Fig. 1. Flow diagram of literature search of the systematic review of IL-6 and CRP in SSc. ceptibility (22). For IL-6, SSc patients who have homozygous GG SNPs of RA (14). CRP, an acute phase response the inception through May 30, 2013 us- the -597 region of the IL-6 promoter protein produced prominently under the ing the following key words: (systemic gene (IL-6 pr) have higher disease ac- transcriptional control by IL-6, serves sclerosis OR scleroderma) AND inter- tivity and worse functional scores than as an assessment of disease activity in leukin-6 (IL-6); and (systemic sclerosis the heterozygous GA patients (23). many inflammatory conditions (15). OR scleroderma) AND C-reactive pro- SNPs in Toll-like receptor 2 (TLR2) CRP is correlated with serum levels tein (CRP). Publications were deemed genes (Pro631His) are associated with of IL-6 in RA (16) and is a surrogate relevant to this review if they reported anti-topoisomerase (Scl70) positivity, marker in RA for disease activity and results from in vitro or in vivo studies, dcSSc subset, and the development of increased erosions (17), whereas in animal models, observational cohorts, pulmonary artery hypertension (PAH). SLE, CRP is used more to predict active clinical studies/trials, and both positive This variant influences TLR-2–mediat- infection rather than an exacerbation of and negative studies regarding IL-6 or ed cell responses in monocyte-derived SLE (18). CRP in SSc were reviewed. Publications dendritic cells to produce increased We previously concisely reviewed the were excluded if they were irrelevant, levels of TNF-α and IL-6 (24). The importance of IL-6 in SSc; construct- review articles, letters to the editors, or GGC allelic combination rs2069827- ing a diagram of signalling from vari- did not study systemic sclerosis. Thus rs1800795-rs2069840 of IL-6 gene has ous cell types in SSc (19). We have reports on morphea were not included. an association with overall SSc suscep- also published the importance of CRP tibility (25) but neither selected SNPs in data from the Canadian Scleroderma Results of the IL-6 receptor (IL-6R) gene nor Research Group (CSRG) where el- An overview of the literature search is CRP gene showed an association with evated CRP was especially prevalent found in Figure 1. Ultimately, 156 rele- overall SSc susceptibility (26, 27). in early dcSSc and was associated with vant articles were chosen for the review. SSc disease activity, severity, and poor 2. Scleroderma animal models survival (20). The purpose of this ex- 1. Genetic susceptibility to and interleukin-6 tensive systematic literature review scleroderma in part of interleukin-6 There are no exact animal models of was to address the overall and organ- and C-reactive protein SSc where the spectrum of autoanti- specific significance of IL-6 and CRP Multiple genes are involved in immune bodies, inflammation, fibrosis and vas- in SSc and potential therapeutic targets regulation affecting Th1/Th2 cytokines cular changes are fully manifest. How- that decrease IL-6 in active SSc. production and balance via regulation ever, SSc animal models give insights of T helper cell differentiation and ac- into pathogenesis of SSc and can be Methods tivation. Single nucleotide polymor- divided into 4 inter-related categories We conducted a systematic review of phisms (SNPs) variants in Signal Trans- the literature to determine the signifi- ducer and Activator of Transcription 2.1. Role of IL-6 trans-signalling in cance and clinical application of IL-6 4 (STAT4) and T-box expressed in T fibrogenesis and CRP in SSc. We searched for Eng- cell 21 (TBX21) that regulate Th1 cells Mouse models studying the role of IL-6 lish-language original articles indexed though promotion of Th1 cytokines trans-signalling in fibrogenic responses in PubMed, Scopus, and Medline from and suppression of Th2 cytokines are are summarised in Table I. S-123 REVIEW IL-6 and CRP in SSc / C. Muangchan & J.E. Pope Table I. Role of IL-6 trans-signalling in fibrogenesis. Animal models Characteristics Interventions Results Subcutaneous injection with BLM mouse model (28) WT C57BL/6 mice # serum IL-6 levels Anti- mIL-6R mAb $ dermal
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