N-(2-hydroxy phenyl) acetamide: a novel suppressor of Toll-like receptors (TLR-2 and TLR-4) in adjuvant-induced arthritic rats
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Toll-like receptors (TLRs) are key recognition structures of immune system and recently emerged as potential contributors to the inflammation observed in human and rodent models of arthritis. Present study aims to investigate the effect of N-(2-hydroxy phenyl)-acetamide (NA-2) on modulation of TLRs in the development of adjuvant-induced arthritis. Arthritis was induced by intradermal administration of heat-killed Mycobacterium tuberculosis H37Ra. The treatment of NA-2 (5 mg/kg) and indomethacin (5 mg/kg) was started in their respective group on the day of arthritis induction. Body weights, paw volume measurements, and nociception sensation (Plantar test) were done on alternate days to monitor the progression of the disease until arthritis score of four was observed in arthritic control group. Along with the clinical signs, histopathology of knee joints was also performed. The splenocytes cultures were prepared from each group; TLR-2 and TLR-4 mRNAs were analyzed in 48-h cultured splenocytes using RT-PCR; and the supernatants were used to determine IL-1β and TNF-α by ELISA. A significant reversal of deficit seen in body weights of the arthritic control group was observed in NA-2-treated animals with a parallel decrease in paw edema and transmission of nociception. Remission of the clinical signs and nociception was associated with improved histology. Compared with arthritic control, NA-2 treatment significantly decreased the level of IL-1β (p < 0.003) and TNF-α (p < 0.001) in the supernatants of cultured splenocytes. Likewise, NA-2 also reduced the expression of TLRs mRNA. Our findings suggest that NA-2 affects AIA in a pleiotropic manner, suppressing TLRs-mediated joint inflammation and related symptoms.
KeywordsToll-like receptor Tumor necrosis factor Interleukin-1 Inflammation N-(2-hydroxy phenyl) acetamide Rheumatoid arthritis
Conflicts of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
- 4.Ji H, Ohmura K, Mahmood U, Lee DM, Hofhuis FM, Boackle SA, Takahashi K, Holers VM, Walport M, Gerard C, Ezekowitz A, Carroll MC, Brenner M, Weissled RV, Erbeek JS, Duchatelle V, Degott C, Benoist C, Mathis D (2002) Arthritis critically dependent on innate immune system players. Immunity 16:157–168PubMedCrossRefGoogle Scholar
- 6.Bobacz K, Sunk IG, Hofstaetter JG, Amoyo L, Toma CD, Akira S, Weichhart TM, Saemann M, Smolen JS (2007) Toll-like receptors and chondrocytes: the lipopolysaccharide-induced decrease in cartilage matrix synthesis is dependent on the presence of Toll-like receptor 4 and antagonized by bone morphogenetic protein 7. Arthritis Rheum 56:1880–1893PubMedCrossRefGoogle Scholar
- 11.Schaefer L, Babelova A, Kiss E, Hausser HJ, Baliova M, Krzyzankova M, Marsche G, Young MF, Mihalik D, Götte M, Malle E, Schaefer RM, Gröne HJ (1991) The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J Clin Invest 115:2223–2233CrossRefGoogle Scholar
- 19.Radstake TR, Roelofs MF, Jenniskens YM, Oppers-Walgreen B, van Riel PL, Barrera P, Joosten LA, van den Berg WB (2004) Expression of Toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin- 18 via interferon γ. Arthritis Rheum 50:3856–3865PubMedCrossRefGoogle Scholar
- 22.Ospelt C, Brentano F, Rengel Y, Stanczyk J, Kolling C, Tak PP, Gay RE, Gay S, Kyburz D (2008) Over expression 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 58:3684–3692PubMedCrossRefGoogle Scholar
- 31.Santana-Sabagun E, Weisman MH (2001) Nonsteroidal anti-inflammatory drugs. In: Ruddy S, Harris JED, Sledge CB, Budd RC, Sergent JS (eds) W.B. Kelly’s textbook of rheumatology, vol 1. Saunders Company, Philadelphia, pp 799–822Google Scholar
- 34.Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R et al (2006) The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 54:26–37PubMedCrossRefGoogle Scholar
- 40.Liesu M, Wenhua Z, Congshan J, Xiaojing H, Weikun H, Fang Z, Rikard H, Shemin L (2010) Toll-like receptor 3 upregulation In macrophages participates in the initiation and maintenance of pristane-induced arthritis in rats. Arth Res Therapy 12.doi: 10.1186/ar3034
- 43.Ji H, Ohmura K, Mahmood U, Lee DM, Hofhuis FM, Boackle SA, Takahashi K, Holers VM, Walport M, Gerard C, Ezekowit A, Carroll MC, Brenner M, Weissleder R, Verbeek JS, Duchatelle V, Degott C, Benoist C, Mathis D (2002) Arthritis critically dependent on innate immune system players. Immunity 16:157–168PubMedCrossRefGoogle Scholar