Rheumatol Int (2014) 34:1613–1614 DOI 10.1007/s00296-013-2890-1

LETTER TO THE EDITOR

Toll‑like receptor‑4 signaling: a new potential therapeutic pathway for rheumatoid arthritis Xiaofeng Li · Tao Xu · Yarui Wang · Cheng Huang · Jun Li 

Received: 10 September 2013 / Accepted: 21 October 2013 / Published online: 20 February 2014 © Springer-Verlag Berlin Heidelberg 2014

Abstract  The Toll-like receptor-4 signaling (TLR-4) has been found to be over-expressed in rheumatoid arthritis (RA) synovium. Furthermore, it regulates the expression of pro-inflammatory cytokines. Based on the current evidences, TLR-4 may be a new potential therapeutic pathway for RA. Keywords  The toll-like receptor-4 signaling · Rheumatoid arthritis · Pro-inflammatory cytokines

Comments We read with great interest the article “Association of TLR4 gene non-missense single nucleotide polymorphisms with rheumatoid arthritis (RA) in Chinese Han population” published in rheumatology international [1]. In this work, Yang H et al. demonstrated that polymorphisms located in the regulatory region of toll-like receptor-4 (TLR-4) were associated with RA. Moreover, the minor allele C and homozygotic variant genotype CC of 3′ UTR SNP rs41426344 and minor allele C of 3′ UTR SNP rs7873784 were identified to be risk factors for the development of RA in Chinese Han people. To date, RA is characterized by tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone [2]. Although the exact causes of RA remain unknown, immunological dysregulation by inflammatory cytokines has been shown to be involved in

X. Li · T. Xu · Y. Wang · C. Huang · J. Li (*)  School of Pharmacy, Anhui Medical University, Mei Shan Road, Hefei 230032, Anhui Province, China e-mail: [email protected]; [email protected]

driving the inflammation and synovial cell proliferation that result in joint destruction in RA patients. The latest achievement obviously suggested that activation by TLR ligands might contribute to the persistent expression of pro-inflammatory cytokines by macrophages and the joint damage to cartilage and bone that occurred in RA. It was well known that TLR-1 to TLR-5 was expressed in RA synovial tissues. Notably, TLR-4 was highly expressed in early and longstanding RA [3]. The proinflammatory cytokines play a dual role in the pathogenesis of RA, which can promote inflammation and destruction of bone. However, TLR-4 can regulate proinflammatory cytokines, including TNF-α, IL-1, IL-6, IL-10 and matrix metalloproteinases (MMP) [4–7]. Coincidentally, celastrol exerts would inhibit LPS-induced RA-FLS migration and invasion by suppressing TLR-4/NF-κB-mediated MMP-9 expression [7]. Similarly, Xu W et al. [8] also found that bauhinia championii extraction could regulate the expression of TLR-4/NF-κB and MyD88 and significantly suppress paw swelling in RA. Taken together, TLR-4 would contribute to the persistent expression of pro-inflammatory cytokines and accelerate inflammation and destruction of bone in RA. It may be involved in regulating the expression of pro-inflammatory cytokines in the pathogenesis of RA. In summary, it would be a valuable to provide a potential association between TLR-4 and RA. We agree that these findings provide additional useful information for clinical practice. However, further studies are required to comprehensively explore the role of TLR-4 in RA, and the development of therapeutic agents targeting TLR-4 may result in significant and innovative therapies for RA. Acknowledgments  This project was supported by grants from the National Natural Science Foundation of China (81072686; 81273526).

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1614 Conflict of interest  We declare that we have no conflict of interest.

References 1. Yang H, Wei C, Li Q, Shou T, Yang Y, Xiao C, Yu M, Li M, Yang Z, Zhang J, Zheng B (2013) Association of TLR4 gene non-missense single nucleotide polymorphisms with rheumatoid arthritis in Chinese Han population. Rheumatol Int 33(5):1283–1288. doi:10.1007/s00296-012-2536-8 2. Feldmann M, Brennan FM, Maini RN (1996) Rheumatoid arthritis. Cell 85(3):307–310 3. Ospelt C, Brentano F, Rengel Y, Stanczyk J, Kolling C, Tak PP, Gay RE, Gay S, Kyburz D (2008) 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. Arthr Rheum 58(12):3684–3692. doi:10.1002/ art.24140 4. Abdollahi-Roodsaz S, Joosten LA, Koenders MI, Devesa I, Roelofs MF, Radstake TR, Heuvelmans-Jacobs M, Akira S, Nicklin MJ, Ribeiro-Dias F, van den Berg WB (2008) Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J Clin Invest 118(1):205–216. doi:10.1172/JCI32639

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Rheumatol Int (2014) 34:1613–1614 5. Philippe L, Alsaleh G, Pichot A, Ostermann E, Zuber G, Frisch B, Sibilia J, Pfeffer S, Bahram S, Wachsmann D, Georgel P (2013) MiR-20a regulates ASK1 expression and TLR4-dependent cytokine release in rheumatoid fibroblast-like synoviocytes. Ann Rheum Dis 72(6):1071–1079. doi:10.1136/annrheum dis-2012-201654 6. Kowalski ML, Wolska A, Grzegorczyk J, Hilt J, Jarzebska M, Drobniewski M, Synder M, Kurowski M (2008) Increased responsiveness to toll-like receptor 4 stimulation in peripheral blood mononuclear cells from patients with recent onset rheumatoid arthritis. Mediat Inflamm 2008:132732. doi:10.1155/2008/132732 7. Li G, Liu D, Zhang Y, Qian Y, Zhang H, Guo S, Sunagawa M, Hisamitsu T, Liu Y (2013) Celastrol inhibits lipopolysaccharide-stimulated rheumatoid fibroblast-like synoviocyte invasion through suppression of TLR4/NF-kappaB-mediated matrix metalloproteinase-9 expression. PLoS ONE 8(7):e68905. doi:10.1371/journal.pone.0068905 8. Xu W, Chu K, Li H, Zhang Y, Huang M, Zheng H, Sha M, Zhang X, Chen L (2013) Bauhinia championii extraction treatment of collagen-induced arthritis via downregulation of the expression of TLR4, MyD88 and NF-kappaB. Am J Chin Med 41(2):379– 390. doi:10.1142/S0192415X13500286

Toll-like receptor-4 signaling: a new potential therapeutic pathway for rheumatoid arthritis.

The Toll-like receptor-4 signaling (TLR-4) has been found to be over-expressed in rheumatoid arthritis (RA) synovium. Furthermore, it regulates the ex...
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