Evaluation of Toll-like Receptor 2 Gene Expression in Rheumatoid Arthritis and Correlation with the Disease Activity

Author(s): Mai Nasser, Noha M. Hazem*, Amany Atwa, Amina Baiomy.

Journal Name: Current Chemical Biology

Volume 13 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Rheumatoid Arthritis (RA) is an autoimmune, chronic, and systematic disease. It affects joints and bones. The exact etiology of RA is still unclear. Varied genetic and environmental factors have been associated with the increased risk for RA. Overactivation of Toll-Like Receptors (TLRs) could initiate the development of autoimmune diseases including RA.

Objective: The aim of the study was to evaluate TLR2 gene expression in rheumatoid arthritis patients and investigate its correlation with the disease activity.

Materials and Methods: This study included 60 patients and 20 healthy individuals. The patients were diagnosed with RA according to the 2010 American College of Rheumatology/ European League Against Rheumatism criteria (ACR/EULAR). All included subjects did not have any joint disorders and /or autoimmune diseases. RA disease activity was determined by the disease activity score of 28 joints. Whole blood was collected from all participants. Total RNA extraction was done. TLR2 mRNA expression was assessed by reverse transcription-PCR (RT-PCR).

Results: TLR2 mRNA expression was found to be significantly higher in RA patients compared to healthy controls. Also, a strong positive correlation was found between TLR2 expression level and the disease activity score. A non significant positive correlation was found between TLR2 expression and serum Rheumatoid Factor (RF) level.

Conclusion: TLR2 pathway may have an important role in RA pathogenesis and could be a new biomarker for diagnosis and monitoring disease activity.

Keywords: Rheumatoid arthritis, TLR2, gene expression, disease activity score, RA pathogenesis, autoimmune disease.

Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010; 376(9746): 1094-108.
Choy E. Understanding the dynamics: Pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology 2012; 51(Suppl. 5): v3-v11.
Smolen JS, Aletaha D, Mcinnes IB. Rheumatoid arthritis. Lancet 2016; 388(10055): 2023-38.
Ortona E, Pierdominici M, Maselli A, Veroni C, Aloisi F, Shoenfeld Y. Sex-based differences in autoimmune diseases. Ann Ist Super Sanita 2016; 52(2): 205-12.
Estruch M, Bancells C, Beloki L, Sanchez-Quesada JL. Ordonez- Llanos J, Benitez S. CD14 and TLR4 mediate cytokine release promoted by electronegative LDL in monocytes. Atherosclerosis 2013; 229(2): 356-62.
Tang CH, Hsu CJ, Yang WH, Fong YC. Lipoteichoic acid enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, PKCdelta and c-Src dependent pathways. Biochem Pharmacol 2010; 79: 1648-57.
Chovanova L, Vlcek M, Krskova K, et al. Increased production of IL-6 and IL-17 in lipopolysaccharide-stimulated peripheral mononuclears from patients with rheumatoid arthritis. Gen Physiol Biophys 2013; 32: 395-404.
Miettinen M, Sareneva T, Julkunen I, Matikainen S. IFNs activate toll-like receptor gene expression in viral infections. Genes Immun 2001; 2: 349-55.
Krutzik SR, Ochoa MT, Sieling PA, et al. Activation and regulation of toll-like receptors 2 and 1 in human leprosy. Nat Med 2003; 9: 525-32.
Imasato A, Desbois-Mouthon C, Han J, et al. Inhibition of p38 MAPK by glucocorticoids via induction of MAPK phosphatase-1 enhances nontypeable Haemophilus influenzae-induced expression of toll-like receptor 2. J Biol Chem 2002; 277: 47444-50.
Shuto T, Imasato A, Jono H, et al. Glucocorticoids synergistically enhance nontypeable Haemophilus influenzae-induced toll-like receptor 2 expression via a negative cross-talk with p38 MAP kinase. J Biol Chem 2002; 277: 17263-70.
Galon J, Franchimont D, Hiroi N, et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 2002; 16: 61-71.
Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: Update on toll-like receptors. Nat Immunol 2010; 11(5): 373-84.
Radstake TR, Roelofs MF, Jenniskens YM, et al. Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferongamma. Arthritis Rheum 2004; 50: 3856-65.
Ospelt C, Brentano F, Rengel Y. Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: Toll-like receptor expression in early and longstanding arthritis. Arthritis Rheum 2008; 58(12): 3684-92.
Foster W, Carruthers D, Lip GY, Blann AD. Inflammatory cytokines, endothelial markers and adhesion molecules in rheumatoid arthritis: Effect of intensive anti-inflammatory treatment. J Thromb Thrombolysis 2010; 29(4): 437-42.
Iwahashi M, Yamamura M, Aita T, et al. Expression of toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis. Arthritis Rheum 2004; 50: 1457-67.
Roelofs MF, Joosten LA, Abdollahi-Roodsaz S, et al. The expression of toll-like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll-like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells. Arthritis Rheum 2005; 52(8): 2313-22.
Seibl R, Birchler T, Loeliger S. Expression and regulation of toll-like receptor 2 in rheumatoid arthritis synovium. Am J Pathol 2003; 162(4): 1221-7.
Huang Q, Ma Y, Adebayo A, Pope RM. Increased macrophage activation mediated through toll-like receptors in rheumatoid arthritis. Arthritis Rheum 2007; 56(7): 2192-201.
Shi B, Huang Q, Tak PP, et al. SNAPIN: An endogenous toll-like receptor ligand in rheumatoid arthritis. Ann Rheum Dis 2012; 71(8): 1411-7.
Aletaha D, Neogi T, Silman AJ, et al. Rheumatoid arthritis classification criteria: An american college of rheumatology/european league against rheumatism collaborative initiative. Ann Rheum Dis 2010; 62(9): 2569-81.
Prevoo MLL, van’t Hof MA, Kuper HH, van de Putte LBA, van Riel PLCM. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38: 44-8.
Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012; 9: 671-5.
O’Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in toll-like receptor signaling. Nat Rev Immunol 2007; 7: 353-64.
Lorenz W, Buhrmann C, Mobasheri A, Lueders C, Shakibaei M. Bacterial lipopolysaccharides form procollagen-endotoxin complexes that trigger cartilage inflammation and degeneration: Implications for the development of rheumatoid arthritis. Arth Res Ther 2013; 15: R111.
Kyburz D, Rethage J, Seibl R, et al. Bacterial peptidoglycans but not CpG oligodeoxynucleotides activate synovial fibroblasts by toll-like receptor signaling. Arthritis Rheum 2003; 48(3): 642-50.
Goldstein RS, Bruchfeld A, Yang L, et al. Cholinergic anti-inflammatory pathway activity and high mobility group box-1 (HMGB1) serum levels in patients with rheumatoid arthritis. Mol Med 2007; 13(3-4): 210-5.
Brentano F, Kyburz D, Schorr O, Gay R, Gay S. The role of toll-like receptor signalling in the pathogenesis of arthritis. Cell Immunol 2005; 233: 90-6.
Chen Y, Sun W, Gao R, et al. The role of high mobility group box chromosomal protein 1 in rheumatoid arthritis. Rheumatology (Oxford) 2013; 52: 1739-47.
Hu F, Mu R, Zhu J, et al. Hypoxia and hypoxia-inducible factor-1alpha provoke toll-like receptor signalling-induced inflammation in rheumatoid arthritis. Ann Rheum Dis 2014; 73: 928-36.
Huang QQ, Koessler RE, Birkett R, et al. Glycoprotein 96 perpetuates the persistent inflammation of rheumatoid arthritis. Arthritis Rheum 2012; 64: 3638-48.
He Z, Shotorbani SS, Jiao Z, et al. HMGB1 promotes the differentiation of Th17 via up-regulating TLR2 and IL-23 of CD14+ monocytes from patients with rheumatoid arthritis. Scand J Immunol 2012; 76: 483-90.
De Rycke L, Verhelst X, Kruithof E, et al. Rheumatoid factor, but not anti-cyclic citrullinated peptide antibodies, is modulated by infliximab treatment in rheumatoid arthritis. Ann Rheum Dis 2005; 64: 299-302.
Lacerte P, Brunet A, Egarnes B, Duchêne B, Brown JP. Overexpression of TLR2 and TLR9 on monocyte subsets of active rheumatoid arthritis patients contributes to enhance responsiveness to TLR agonists. Arth Res Ther 2016; 18(10): 1-14.
Eser B, Sahin N. Evaluation of tool-like receptor-2 and 4 and interleukin-6 gene expressions in Turkish rheumatoid arthritis patients. Clin Rheumatol 2016; 35(11): 2693-7.
Neumann E, Lefevre S, Zimmermann B, Gay S, Muller-Ladner U. Rheumatoid arthritis progression mediated by activated synovial fibroblasts. Trends Mol Med 2010; 16: 458-68.
Kim K, Cho M, Lee S, et al. Human rheumatoid synovial fibroblasts promote osteoclastogenic activity by activating RANKL via TLR-2 and TLR-4 activation. Immunol Lett 2007; 110: 54-64.
Schrijver IA, Melief MJ, Tak PP, Hazenberg MP, Laman JD. Antigen- presenting cells containing bacterial peptidoglycan in synovial tissues of rheumatoid arthritis patients coexpress costimulatory molecules and cytokines. Arthritis Rheum 2000; 43: 2160-8.
Sacre SM, Andreakos E, Kiriakidis S, et al. The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. Am J Pathol 2007; 170: 518-25.
Philippe L, Alsaleh G, Suffert G, et al. TLR2 expression is regulated by microRNA miR-19 in rheumatoid fibroblast-like synoviocytes. J Immunol 2011; 188: 454-61.
Yokota K, Miyazaki T, Hemmatazad H, et al. The pattern-recognition receptor nucleotide-binding oligomerization domain- containing protein 1 promotes production of inflammatory mediators in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 2012; 64: 1329-37.
Saber T, Veale DJ, Balogh E, et al. Toll-like receptor 2 induced angiogenesis and invasion is mediated through the Tie2 signalling pathway in rheumatoid arthritis. PLoS One 2011; 6e23540

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [140 - 148]
Pages: 9
DOI: 10.2174/2212796813666181219124924
Price: $58

Article Metrics

PDF: 42
PRC: 1