Evaluation of TAK-242 (Resatorvid) Effects on Inflammatory Status of Fibroblast-like Synoviocytes in Rheumatoid Arthritis and Trauma Patients
-
Jafar Karami
,
Elham Farhadi
,
Ali-Akbar Delbandi
,
Mehdi Shekarabi
,
Mohammad Naghi Tahmasebi
,
Arash Sharafat Vaziri
,
Maryam Akhtari
,
Mohammad Javad Mousavi
,
Ahmadreza Jamshidi
,
Mahdi Mahmoudi
Abstract
Fibroblast-like synoviocytes (FLSs) produce lots of inflammatory molecules that trigger immune responses and intensification the inflammation and thereby play important roles in Rheumatoid Arthritis )RA( pathogenesis. Due to the important roles of toll-like receptor 4 (TLR4) in cytokine production and inflammation, we aimed to evaluate the effects of TAK-242 (Resatorvid) on interleukin (IL)1-β, IL-6, TNF-α, and TLR4 expression and two important proteins of nuclear factor-κB (NF-κB) signaling pathway (Ikβα and pIkβα) in RA and trauma FLSs.
FLSs were isolated from synovial tissues of trauma (n=10) and RA (n=10) patients and cultured in Dulbecco's Modified Eagle Medium (DMEM). 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) was performed to evaluate the cytotoxicity effects of TAK-242 on the RA FLSs. Real-time PCR was performed to measure the expression level of IL1-β, IL-6, TNF-α, and TLR4 genes in Lipopolysaccharide (LPS) and TAK-242 treated FLSs. Furthermore, the treated FLSs were evaluated for protein levels of Ikβα and pIkβα by western blot.
The baseline expression of IL1-β, IL-6, TNF-α, and TLR4 showed no significant differences between healthy and RA FLSs. LPS stimulated FLSs significantly increased mRNA levels of IL-1β, IL-6, TNF-α, and TLR4 genes in both the healthy and RA FLSs compared with that of their control groups, and pretreatment with TAK-242 reversed the effect. Furthermore, LPS-stimulated FLSs significantly increased the level of pIkβα in both the healthy and RA FLSs compared with that of their control groups, and pretreatment with TAK-242 reversed the effect.
We provide the data that TAK-242 through inhibiting the NF-κB signaling pathway may modulate TLR4-mediated inflammatory responses and could be considered as a potential therapeutic agent for RA patients.
1. Scherer HU, Häupl T, Burmester GR. The etiology of rheumatoid arthritis. Journal of autoimmunity. 2020;110:102400.
2. Okada Y, Nakanishi I, Kajikawa K. Ultrastructure of the mouse synovial membrane. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1981;24(6):835-43.
3. Wilkinson LS, Pitsillides AA, Worrall JG, Edwards JC. Light microscopic characterization of the fibroblast‐like synovial intimal cell (synoviocyte). Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1992;35(10):1179-84.
4. Smith M, Barg E, Weedon H, Papengelis V, Smeets T, Tak P, et al. Microarchitecture and protective mechanisms in synovial tissue from clinically and arthroscopically normal knee joints. Annals of the rheumatic diseases. 2003;62(4):303-7.
5. Lee DM, Kiener HP, Agarwal SK, Noss EH, Watts GF, Chisaka O, et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science. 2007;315(5814):1006-10.
6. Kiener HP, Watts GF, Cui Y, Wright J, Thornhill TS, Sköld M, et al. Synovial fibroblasts self‐direct multicellular lining architecture and synthetic function in three‐dimensional organ culture. Arthritis & Rheumatism. 2010;62(3):742-52.
7. Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nature Reviews Rheumatology. 2013;9(1):24.
8. Turner JD, Filer A. The role of the synovial fibroblast in rheumatoid arthritis pathogenesis. Current opinion in rheumatology. 2015;27(2):175-82.
9. Tolboom T, van der Helm-van Mil A, Nelissen R, Breedveld F, Toes R, Huizinga T. The invasiveness of fibroblast-like synoviocytes is of relevance for the rate of joint destruction in patients with rheumatoid arthritis and is a patient characteristic. Arthritis Research & Therapy. 2005;7(1):1.
10. Masoumi M, Mehrabzadeh M, Mahmoudzehi S, Mousavi MJ, Jamalzehi S, Sahebkar A, et al. Role of glucose metabolism in aggressive phenotype of fibroblast-like synoviocytes: Latest evidence and therapeutic approaches in rheumatoid arthritis. International Immunopharmacology. 2020;89:107064.
11. Karami J, Masoumi M, Khorramdelazad H, Bashiri H, Darvishi P, Sereshki HA, et al. Role of autophagy in the pathogenesis of rheumatoid arthritis: Latest evidence and therapeutic approaches. Life Sciences. 2020:117734.
12. Masoumi M, Bashiri H, Khorramdelazad H, Barzaman K, Hashemi N, Sereshki HA, et al. Destructive Roles of Fibroblast-like Synoviocytes in Chronic Inflammation and Joint Damage in Rheumatoid Arthritis. Inflammation. 2020:1-14.
13. Sweeney S, Firestein G. Mitogen activated protein kinase inhibitors: where are we now and where are we going? Annals of the rheumatic diseases. 2006;65(suppl 3):iii83-iii8.
14. Hammaker D, Sweeney S, Firestein G. Signal transduction networks in rheumatoid arthritis. Annals of the rheumatic diseases. 2003;62(suppl 2):ii86-ii9.
15. Sweeney SE, Firestein GS. Primer: signal transduction in rheumatic disease—a clinician's guide. Nature Clinical Practice Rheumatology. 2007;3(11):651-60.
16. Tak PP, Firestein GS. NF-κB: a key role in inflammatory diseases. The Journal of clinical investigation. 2001;107(1):7-11.
17. Xu D, Yan S, Wang H, Gu B, Sun K, Yang X, et al. IL-29 enhances LPS/TLR4-mediated inflammation in rheumatoid arthritis. Cellular Physiology and Biochemistry. 2015;37(1):27-34.
18. Gierut A, Perlman H, Pope RM. Innate immunity and rheumatoid arthritis. Rheumatic Disease Clinics. 2010;36(2):271-96.
19. Alonso-Pérez A, Franco-Trepat E, Guillán-Fresco M, Jorge-Mora A, López V, Pino J, et al. Role of toll-like receptor 4 on osteoblast metabolism and function. Frontiers in physiology. 2018;9:504.
20. Pierer M, Wagner U, Rossol M, Ibrahim S. Toll-like receptor 4 is involved in inflammatory and joint destructive pathways in collagen-induced arthritis in DBA1J mice. PloS one. 2011;6(8):e23539.
21. Radstake TR, Roelofs MF, Jenniskens YM, Oppers‐Walgreen B, van Riel PL, Barrera P, 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 interferon‐γ. Arthritis & Rheumatism. 2004;50(12):3856-65.
22. Ospelt C, Brentano F, Rengel Y, Stanczyk J, Kolling C, Tak PP, et al. 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 & Rheumatism: Official Journal of the American College of Rheumatology. 2008;58(12):3684-92.
23. Abdollahi-Roodsaz S, Joosten LA, Koenders MI, Devesa I, Roelofs MF, Radstake TR, et al. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. The Journal of clinical investigation. 2008;118(1):205-16.
24. Piao W, Shirey KA, Ru LW, Lai W, Szmacinski H, Snyder GA, et al. A decoy peptide that disrupts TIRAP recruitment to TLRs is protective in a murine model of influenza. Cell reports. 2015;11(12):1941-52.
25. Achek A, Yesudhas D, Choi S. Toll-like receptors: promising therapeutic targets for inflammatory diseases. Archives of pharmacal research. 2016;39(8):1032-49.
26. Matsunaga N, Tsuchimori N, Matsumoto T, Ii M. TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Molecular pharmacology. 2011;79(1):34-41.
27. Humby F, Lewis M, Ramamoorthi N, Hackney JA, Barnes MR, Bombardieri M, et al. Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients. Annals of the rheumatic diseases. 2019;78(6):761-72.
28. Hyrich K, Watson K, Silman A, Symmons D. Predictors of response to anti-TNF-α therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology. 2006;45(12):1558-65.
29. Samarpita S, Kim JY, Rasool MK, Kim KS. Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug. Arthritis research & therapy. 2020;22(1):16.
30. Arnett FC, Edworthy SM, Bloch DA, Mcshane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1988;31(3):315-24.
31. Rosengren S, Boyle DL, Firestein GS. Acquisition, culture, and phenotyping of synovial fibroblasts. Arthritis Research: Springer; 2007. p. 365-75.
32. Mu N, Gu J, Huang T, Zhang C, Shu Z, Li M, et al. A novel NF-κB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis. Scientific reports. 2016;6(1):1-14.
33. Schefe JH, Lehmann KE, Buschmann IR, Unger T, Funke-Kaiser H. Quantitative real-time RT-PCR data analysis: current concepts and the novel “gene expression’s C T difference” formula. Journal of molecular medicine. 2006;84(11):901-10.
34. Takashima K, Matsunaga N, Yoshimatsu M, Hazeki K, Kaisho T, Uekata M, et al. Analysis of binding site for the novel small‐molecule TLR4 signal transduction inhibitor TAK‐242 and its therapeutic effect on mouse sepsis model. British journal of pharmacology. 2009;157(7):1250-62.
35. Rice TW, Wheeler AP, Bernard GR, Vincent J-L, Angus DC, Aikawa N, et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Critical care medicine. 2010;38(8):1685-94.
36. Kuzmich NN, Sivak KV, Chubarev VN, Porozov YB, Savateeva-Lyubimova TN, Peri F. TLR4 signaling pathway modulators as potential therapeutics in inflammation and sepsis. Vaccines. 2017;5(4):34.
37. Monnet E, Choy EH, McInnes I, Kobakhidze T, de Graaf K, Jacqmin P, et al. Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: a phase II study. Annals of the rheumatic diseases. 2020;79(3):316-23.
38. Batool M, Choi S. TLR4-targeting therapeutics: Structural basis and computer-aided drug discovery approaches. Molecules. 2020;25(3):627.
39. Achek A, Shah M, Seo JY, Kwon H-K, Gui X, Shin H-J, et al. Linear and rationally designed stapled peptides abrogate TLR4 pathway and relieve inflammatory symptoms in rheumatoid arthritis rat model. Journal of medicinal chemistry. 2019;62(14):6495-511.
40. Joosten LA, Abdollahi-Roodsaz S, Dinarello CA, O'neill L, Netea MG. Toll-like receptors and chronic inflammation in rheumatic diseases: new developments. Nature Reviews Rheumatology. 2016;12(6):344.
41. Kawamoto T, Ii M, Kitazaki T, Iizawa Y, Kimura H. TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. European journal of pharmacology. 2008;584(1):40-8.
42. Magnani M, Crinelli R, Bianchi M, Antonelli A. The ubiquitin-dependent proteolytic system and other potential targets for the modulation of nuclear factor-kB (NF-kB). Current drug targets. 2000;1(4):387-99.
43. Andreakos E, Sacre S, Foxwell BM, Feldmann M. The toll-like receptor-nuclear factor kappaB pathway in rheumatoid arthritis. Front Biosci. 2005;10:2478-88.
2. Okada Y, Nakanishi I, Kajikawa K. Ultrastructure of the mouse synovial membrane. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1981;24(6):835-43.
3. Wilkinson LS, Pitsillides AA, Worrall JG, Edwards JC. Light microscopic characterization of the fibroblast‐like synovial intimal cell (synoviocyte). Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1992;35(10):1179-84.
4. Smith M, Barg E, Weedon H, Papengelis V, Smeets T, Tak P, et al. Microarchitecture and protective mechanisms in synovial tissue from clinically and arthroscopically normal knee joints. Annals of the rheumatic diseases. 2003;62(4):303-7.
5. Lee DM, Kiener HP, Agarwal SK, Noss EH, Watts GF, Chisaka O, et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science. 2007;315(5814):1006-10.
6. Kiener HP, Watts GF, Cui Y, Wright J, Thornhill TS, Sköld M, et al. Synovial fibroblasts self‐direct multicellular lining architecture and synthetic function in three‐dimensional organ culture. Arthritis & Rheumatism. 2010;62(3):742-52.
7. Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nature Reviews Rheumatology. 2013;9(1):24.
8. Turner JD, Filer A. The role of the synovial fibroblast in rheumatoid arthritis pathogenesis. Current opinion in rheumatology. 2015;27(2):175-82.
9. Tolboom T, van der Helm-van Mil A, Nelissen R, Breedveld F, Toes R, Huizinga T. The invasiveness of fibroblast-like synoviocytes is of relevance for the rate of joint destruction in patients with rheumatoid arthritis and is a patient characteristic. Arthritis Research & Therapy. 2005;7(1):1.
10. Masoumi M, Mehrabzadeh M, Mahmoudzehi S, Mousavi MJ, Jamalzehi S, Sahebkar A, et al. Role of glucose metabolism in aggressive phenotype of fibroblast-like synoviocytes: Latest evidence and therapeutic approaches in rheumatoid arthritis. International Immunopharmacology. 2020;89:107064.
11. Karami J, Masoumi M, Khorramdelazad H, Bashiri H, Darvishi P, Sereshki HA, et al. Role of autophagy in the pathogenesis of rheumatoid arthritis: Latest evidence and therapeutic approaches. Life Sciences. 2020:117734.
12. Masoumi M, Bashiri H, Khorramdelazad H, Barzaman K, Hashemi N, Sereshki HA, et al. Destructive Roles of Fibroblast-like Synoviocytes in Chronic Inflammation and Joint Damage in Rheumatoid Arthritis. Inflammation. 2020:1-14.
13. Sweeney S, Firestein G. Mitogen activated protein kinase inhibitors: where are we now and where are we going? Annals of the rheumatic diseases. 2006;65(suppl 3):iii83-iii8.
14. Hammaker D, Sweeney S, Firestein G. Signal transduction networks in rheumatoid arthritis. Annals of the rheumatic diseases. 2003;62(suppl 2):ii86-ii9.
15. Sweeney SE, Firestein GS. Primer: signal transduction in rheumatic disease—a clinician's guide. Nature Clinical Practice Rheumatology. 2007;3(11):651-60.
16. Tak PP, Firestein GS. NF-κB: a key role in inflammatory diseases. The Journal of clinical investigation. 2001;107(1):7-11.
17. Xu D, Yan S, Wang H, Gu B, Sun K, Yang X, et al. IL-29 enhances LPS/TLR4-mediated inflammation in rheumatoid arthritis. Cellular Physiology and Biochemistry. 2015;37(1):27-34.
18. Gierut A, Perlman H, Pope RM. Innate immunity and rheumatoid arthritis. Rheumatic Disease Clinics. 2010;36(2):271-96.
19. Alonso-Pérez A, Franco-Trepat E, Guillán-Fresco M, Jorge-Mora A, López V, Pino J, et al. Role of toll-like receptor 4 on osteoblast metabolism and function. Frontiers in physiology. 2018;9:504.
20. Pierer M, Wagner U, Rossol M, Ibrahim S. Toll-like receptor 4 is involved in inflammatory and joint destructive pathways in collagen-induced arthritis in DBA1J mice. PloS one. 2011;6(8):e23539.
21. Radstake TR, Roelofs MF, Jenniskens YM, Oppers‐Walgreen B, van Riel PL, Barrera P, 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 interferon‐γ. Arthritis & Rheumatism. 2004;50(12):3856-65.
22. Ospelt C, Brentano F, Rengel Y, Stanczyk J, Kolling C, Tak PP, et al. 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 & Rheumatism: Official Journal of the American College of Rheumatology. 2008;58(12):3684-92.
23. Abdollahi-Roodsaz S, Joosten LA, Koenders MI, Devesa I, Roelofs MF, Radstake TR, et al. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. The Journal of clinical investigation. 2008;118(1):205-16.
24. Piao W, Shirey KA, Ru LW, Lai W, Szmacinski H, Snyder GA, et al. A decoy peptide that disrupts TIRAP recruitment to TLRs is protective in a murine model of influenza. Cell reports. 2015;11(12):1941-52.
25. Achek A, Yesudhas D, Choi S. Toll-like receptors: promising therapeutic targets for inflammatory diseases. Archives of pharmacal research. 2016;39(8):1032-49.
26. Matsunaga N, Tsuchimori N, Matsumoto T, Ii M. TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Molecular pharmacology. 2011;79(1):34-41.
27. Humby F, Lewis M, Ramamoorthi N, Hackney JA, Barnes MR, Bombardieri M, et al. Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients. Annals of the rheumatic diseases. 2019;78(6):761-72.
28. Hyrich K, Watson K, Silman A, Symmons D. Predictors of response to anti-TNF-α therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology. 2006;45(12):1558-65.
29. Samarpita S, Kim JY, Rasool MK, Kim KS. Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug. Arthritis research & therapy. 2020;22(1):16.
30. Arnett FC, Edworthy SM, Bloch DA, Mcshane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1988;31(3):315-24.
31. Rosengren S, Boyle DL, Firestein GS. Acquisition, culture, and phenotyping of synovial fibroblasts. Arthritis Research: Springer; 2007. p. 365-75.
32. Mu N, Gu J, Huang T, Zhang C, Shu Z, Li M, et al. A novel NF-κB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis. Scientific reports. 2016;6(1):1-14.
33. Schefe JH, Lehmann KE, Buschmann IR, Unger T, Funke-Kaiser H. Quantitative real-time RT-PCR data analysis: current concepts and the novel “gene expression’s C T difference” formula. Journal of molecular medicine. 2006;84(11):901-10.
34. Takashima K, Matsunaga N, Yoshimatsu M, Hazeki K, Kaisho T, Uekata M, et al. Analysis of binding site for the novel small‐molecule TLR4 signal transduction inhibitor TAK‐242 and its therapeutic effect on mouse sepsis model. British journal of pharmacology. 2009;157(7):1250-62.
35. Rice TW, Wheeler AP, Bernard GR, Vincent J-L, Angus DC, Aikawa N, et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Critical care medicine. 2010;38(8):1685-94.
36. Kuzmich NN, Sivak KV, Chubarev VN, Porozov YB, Savateeva-Lyubimova TN, Peri F. TLR4 signaling pathway modulators as potential therapeutics in inflammation and sepsis. Vaccines. 2017;5(4):34.
37. Monnet E, Choy EH, McInnes I, Kobakhidze T, de Graaf K, Jacqmin P, et al. Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: a phase II study. Annals of the rheumatic diseases. 2020;79(3):316-23.
38. Batool M, Choi S. TLR4-targeting therapeutics: Structural basis and computer-aided drug discovery approaches. Molecules. 2020;25(3):627.
39. Achek A, Shah M, Seo JY, Kwon H-K, Gui X, Shin H-J, et al. Linear and rationally designed stapled peptides abrogate TLR4 pathway and relieve inflammatory symptoms in rheumatoid arthritis rat model. Journal of medicinal chemistry. 2019;62(14):6495-511.
40. Joosten LA, Abdollahi-Roodsaz S, Dinarello CA, O'neill L, Netea MG. Toll-like receptors and chronic inflammation in rheumatic diseases: new developments. Nature Reviews Rheumatology. 2016;12(6):344.
41. Kawamoto T, Ii M, Kitazaki T, Iizawa Y, Kimura H. TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. European journal of pharmacology. 2008;584(1):40-8.
42. Magnani M, Crinelli R, Bianchi M, Antonelli A. The ubiquitin-dependent proteolytic system and other potential targets for the modulation of nuclear factor-kB (NF-kB). Current drug targets. 2000;1(4):387-99.
43. Andreakos E, Sacre S, Foxwell BM, Feldmann M. The toll-like receptor-nuclear factor kappaB pathway in rheumatoid arthritis. Front Biosci. 2005;10:2478-88.
| Files | ||
| Issue | Vol 20 No 4 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v20i4.6955 | |
| Keywords | ||
| Rheumatoid arthritis Trauma and stressor related disorders Toll-like receptor 4 | ||
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How to Cite
1.
Karami J, Farhadi E, Delbandi A-A, Shekarabi M, Tahmasebi MN, Sharafat Vaziri A, Akhtari M, Mousavi MJ, Jamshidi A, Mahmoudi M. Evaluation of TAK-242 (Resatorvid) Effects on Inflammatory Status of Fibroblast-like Synoviocytes in Rheumatoid Arthritis and Trauma Patients. Iran J Allergy Asthma Immunol. 2021;20(4):453-464.
