Mechanistic role of redox-active trace metals/Toll like receptor 4-coupled activation in AP-1 signalling pathway in fibroblast-like synovial cells
Main Article Content
Abstract
Reactive oxygen species (ROS) are implicated in playing a role in initiating and in propagating the pathogenesis of rheumatoid arthritis (RA). We investigated the mechanism(s) by which essential redox-active trace metals (RATM) may activate gene transcription in synovial fibroblasts. The rabbit fibroblast-like synovial cells which express Toll-like receptor 4 (TLR4), were used as a model system for potentially initiating RA through oxidative stress. Potassium peroxychromate (PPC, Cr5+), ferrous chloride (FeCl2, Fe2+), and cuprous chloride (CuCl, Cu+) at the indicated valency states were used as exogenous pro-oxidants. These trace metals can induce oxidative stress through TLR4 activation to release inflammatory cytokines and high mobility group box 1 protein. We measured the total expression levels of mitogen-activated protein kinase (MAPK) in the synovial cells and examined the effect of the redox-active trace metals on the time-course production of phosphorylated moieties of MAPK by fluorescence cell-sorting flow cytometry. TLR4 siRNA was used to examine the role of TLR4 in the activator protein -1 (AP-1) signalling activity, and western blots were used to measure the time-course phosphorylation levels of AP-1-activation-related proteins. While the redox-active trace metals increased intracellular ROS that can induce oxidative stress, they also induced MAPK kinases to upregulate the expression of AP-1 proteins in synovial cells. Our results show that redox-active trace metal/TLR4-coupled activation may contribute to the pathogenesis of RA. The signaling pathway by which inflammation and its destructive sequel may occur in RA through synovial cells underlies the need for developing therapeutic agents to serve in individualized RA therapy with a consideration for the underlying mechanism(s) of its pathogenesis.
Keywords:
Redox-active trace metals, Oxidative stress, Rabbit synovial fibroblasts, Activator protein -1, Mitogen-activated protein kinases
Article Details
How to Cite
ALSOUSI, Asmaa A.; IGWE, Orisa J..
Mechanistic role of redox-active trace metals/Toll like receptor 4-coupled activation in AP-1 signalling pathway in fibroblast-like synovial cells.
Medical Research Archives, [S.l.], v. 10, n. 9, sep. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3040>. Date accessed: 05 nov. 2024.
doi: https://doi.org/10.18103/mra.v10i9.3040.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Lajas C, Abasolo L, Bellajdel B, Hernandez-Garcia C, Carmona L, Vargas E, Lazaro P, Jover JA. Costs and predictors of costs in rheumatoid arthritis: a prevalence-based study. Arthritis Rheum. 2003;49(1):64-70.
2. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25.
3. Gibofsky A. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. The American J Managed Care. 2012;18(13 Suppl):S295-302.
4. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205-2219.
5. Noss EH, Brenner MB. The role and therapeutic implications of fibroblast-like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis. Immunological reviews. 2008;223:252-270.
6. Datta S, Kundu S, Ghosh P, De S, Ghosh A, Chatterjee M. Correlation of oxidant status with oxidative tissue damage in patients with rheumatoid arthritis. Clinical rheumatology. 2014;33(11):1557-1564.
7. Kundu S, Ghosh P, Datta S, Ghosh A, Chattopadhyay S, Chatterjee M. Oxidative stress as a potential biomarker for determining disease activity in patients with rheumatoid arthritis. Free Radic Res. 2012;46(12):1482-1489.
8. Schonthaler HB, Guinea-Viniegra J, Wagner EF. Targeting inflammation by modulating the Jun/AP-1 pathway. Ann Rheum Dis. 2011;70 Suppl 1:i109-112.
9. Okamoto H, Cujec TP, Yamanaka H, Kamatani N. Molecular aspects of rheumatoid arthritis: role of transcription factors. The FEBS journal. 2008;275(18):4463-4470.
10. Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cellular signalling. 2001;13(2):85-94.
11. Zenz R, Eferl R, Scheinecker C, Redlich K, Smolen J, Schonthaler HB, Kenner L, Tschachler E, Wagner EF. Activator protein 1 (Fos/Jun) functions in inflammatory bone and skin disease. Arthritis research & therapy. 2008;10(1):201.
12. Zenz R, Wagner EF. Jun signalling in the epidermis: From developmental defects to psoriasis and skin tumors. The international journal of biochemistry & cell biology. 2006;38(7):1043-1049.
13. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410(6824):37-40.
14. Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiological reviews. 2012;92(2):689-737.
15. Harnett MM, Katz E, Ford CA. Differential signalling during B-cell maturation. Immunology letters. 2005;98(1):33-44.
16. Liu JO. The yins of T cell activation. Science's STKE : signal transduction knowledge environment. 2005;2005(265):re1.
17. Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004;21(4):467-476.
18. Moens U, Kostenko S, Sveinbjornsson B. The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinases (MAPKAPKs) in Inflammation. Genes (Basel). 2013;4(2):101-133.
19. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22(2):153-183.
20. Goodridge HS, Harnett W, Liew FY, Harnett MM. Differential regulation of interleukin-12 p40 and p35 induction via Erk mitogen-activated protein kinase-dependent and -independent mechanisms and the implications for bioactive IL-12 and IL-23 responses. Immunology. 2003;109(3):415-425.
21. Nah SS, Won HJ, Ha E, Kang I, Cho HY, Hur SJ, Lee SH, Baik HH. Epidermal growth factor increases prostaglandin E2 production via ERK1/2 MAPK and NF-kappaB pathway in fibroblast like synoviocytes from patients with rheumatoid arthritis. Rheumatology international. 2010;30(4):443-449.
22. Barchowsky A, Frleta D, Vincenti MP. Integration of the NF-kappaB and mitogen-activated protein kinase/AP-1 pathways at the collagenase-1 promoter: divergence of IL-1 and TNF-dependent signal transduction in rabbit primary synovial fibroblasts. Cytokine. 2000;12(10):1469-1479.
23. Yamamoto A, Fukuda A, Seto H, Miyazaki T, Kadono Y, Sawada Y, Nakamura I, Katagiri H, Asano T, Tanaka Y, Oda H, Nakamura K, Tanaka S. Suppression of arthritic bone destruction by adenovirus-mediated dominant-negative Ras gene transfer to synoviocytes and osteoclasts. Arthritis Rheum. 2003;48(9):2682-2692.
24. Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, Manning AM, Firestein GS. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest. 2001;108(1):73-81.
25. Liacini A, Sylvester J, Qing Li W, Huang W, Dehnade F, Ahmad M, Zafarullah M. Induction of matrix metalloproteinase-13 gene expression by TNF-α is mediated by MAP kinases, AP-1, and NF-κB transcription factors in articular chondrocytes. Exp Cell Res. 2003;288(1):208-217.
26. Liacini A, Sylvester J, Li WQ, Zafarullah M. Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix biology : journal of the International Society for Matrix Biology. 2002;21(3):251-262.
27. Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, Woodgett JR. Phosphorylation of c-jun mediated by MAP kinases. Nature. 1991;353(6345):670-674.
28. Han J, Lee JD, Bibbs L, Ulevitch RJ. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science (New York, NY). 1994;265(5173):808-811.
29. Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372(6508):739-746.
30. Herskowitz I. MAP kinase pathways in yeast: for mating and more. Cell. 1995;80(2):187-197.
31. Duch A, de Nadal E, Posas F. The p38 and Hog1 SAPKs control cell cycle progression in response to environmental stresses. FEBS Lett. 2012;586(18):2925-2931.
32. Malemud CJ. Targeted drug development for arthritis. Future Medicinal Chemistry. 2012;4(6):701-703.
33. Karki R, Igwe OJ. Toll-like receptor 4-mediated nuclear factor kappa B activation is essential for sensing exogenous oxidants to propagate and maintain oxidative/nitrosative cellular stress. PLoS ONE. 2013;8(9):e73840.
34. Alsousi AA, Igwe OJ. Redox-active trace metal-induced release of high mobility group box 1(HMGB1) and inflammatory cytokines in fibroblast-like synovial cells is Toll-like receptor 4 (TLR4) dependent. Biochimica et Biophysica Acta (BBA) - Mol Basis of Dis. 2018(11) 3847-3858.
35. Andersson U, Erlandsson-Harris H. HMGB1 is a potent trigger of arthritis. Journal internal medicine. 2004;255(3):344-350.
36. Kokkola R, Sundberg E, Ulfgren AK, Palmblad K, Li J, Wang H, Ulloa L, Yang H, Yan XJ, Furie R, Chiorazzi N, Tracey KJ, Andersson U, Harris HE. High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovitis. Arthritis Rheum. 2002;46(10):2598-2603.
37. Kokkola R, Li J, Sundberg E, Aveberger AC, Palmblad K, Yang H, Tracey KJ, Andersson U, Harris HE. Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis Rheum. 2003;48(7):2052-2058.
38. Miesel R, Kroger H, Kurpisz M, Weser U. Induction of arthritis in mice and rats by potassium peroxochromate and assessment of disease activity by whole blood chemiluminescence and 99mpertechnetate-imaging. Free Radic Res. 1995;23(3):213-227.
39. Alsousi AA, Igwe OJ. Autophagy protects against redox active trace metal (RATM) – induced cell death in rabbit synovial fibroblasts. Exp Cell Res. 2018; 374 (1):19-28.
40. Gu J, Liu Y, Xie B, Ye P, Huang J, Lu Z. Roles of toll-like receptors: From inflammation to lung cancer progression. Biomedical reports. 2018;8(2):126-132.
41. Liu Y, Li T, Xu Y, Xu E, Zhou M, Wang B, Shen J. Effects of TLR4 gene silencing on the proliferation and apotosis of hepatocarcinoma HEPG2 cells. Oncology letters. 2016;11(5):3054-3060.
42. Ahmed A, Redmond HP, Wang JH. Links between Toll-like receptor 4 and breast cancer. Oncoimmunology. 2013;2(2):e22945.
43. Wang L, Zhu R, Huang Z, Li H, Zhu H. Lipopolysaccharide-induced toll-like receptor 4 signaling in cancer cells promotes cell survival and proliferation in hepatocellular carcinoma. Dig Dis Sci. 2013;58(8):2223-2236.
44. Malemud CJ. Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways. Anti-inflammatory & anti-allergy agents in medicinal chemistry. 2011;10(2):78-84.
45. Malemud CJ. Intracellular Signaling Pathways in Rheumatoid Arthritis. J Clin & Cellular Immunol. 2013;4:160.
46. Youssef P, Roth J, Frosch M, Costello P, Fitzgerald O, Sorg C, Bresnihan B. Expression of myeloid related proteins (MRP) 8 and 14 and the MRP8/14 heterodimer in rheumatoid arthritis synovial membrane. J Rheumatol. 1999;26(12):2523-2528.
47. Han Z, Boyle DL, Aupperle KR, Bennett B, Manning AM, Firestein GS. Jun N-terminal kinase in rheumatoid arthritis. J Pharmacol Exp Ther. 1999;291(1):124-130.
48. Dean JL, Sarsfield SJ, Tsounakou E, Saklatvala J. p38 Mitogen-activated protein kinase stabilizes mRNAs that contain cyclooxygenase-2 and tumor necrosis factor AU-rich elements by inhibiting deadenylation. J Biol Chem. 2003;278(41):39470-39476.
49. Alsousi AA , Siddiqui S, Igwe OJ. Cytokine-mediated Differential Regulation of Cyclooxygenase-2, High Mobility Group Box 1 Protein and Matrix Metalloproteinase-9 Expression in Fibroblast-like Synovial Cells. J Clin & Exp Pharmacol. 2017;7(4).
50. Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell. 2000;103(2):239-252.
51. David JP, Sabapathy K, Hoffmann O, Idarraga MH, Wagner EF. JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms. J Cell Sci. 2002;115(Pt 22):4317-4325.
52. Nishina H, Fischer KD, Radvanyi L, Shahinian A, Hakem R, Rubie EA, Bernstein A, Mak TW, Woodgett JR, Penninger JM. Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3. Nature. 1997;385(6614):350-353.
53. Sabapathy K, Jochum W, Hochedlinger K, Chang L, Karin M, Wagner EF. Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2. Mech Dev. 1999;89(1-2):115-124.
54. Tournier C, Dong C, Turner TK, Jones SN, Flavell RA, Davis RJ. MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes & Development. 2001;15(11):1419-1426.
55. Varfolomeev E, Goncharov T, Maecker H, Zobel K, Komuves LG, Deshayes K, Vucic D. Cellular inhibitors of apoptosis are global regulators of NF-kappaB and MAPK activation by members of the TNF family of receptors. Sci Signal. 2012;5(216):ra22.
56. Thiel MJ, Schaefer CJ, Lesch ME, Mobley JL, Dudley DT, Tecle H, Barrett SD, Schrier DJ, Flory CM. Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms. Arthritis Rheum. 2007;56(10):3347-3357.
57. Tagoe CE, Marjanovic N, Park JY, Chan ES, Abeles AM, Attur M, Abramson SB, Pillinger MH. Annexin-1 mediates TNF-alpha-stimulated matrix metalloproteinase secretion from rheumatoid arthritis synovial fibroblasts. J Immunol. 2008;181(4):2813-2820.
58. Hannemann N, Jordan J, Paul S, Reid S, Baenkler HW, Sonnewald S, Bäuerle T, Vera J, Schett G, Bozec A. The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages. J Immunol. 2017;198(9):3605-3614.
59. Dooley S, Herlitzka I, Hanselmann R, Ermis A, Henn W, Remberger K, Hopf T, Welter C. Constitutive expression of c-fos and c-jun, overexpression of ets-2, and reduced expression of metastasis suppressor gene nm23-H1 in rheumatoid arthritis. Ann Rheum Dis. 1996;55(5):298-304.
2. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25.
3. Gibofsky A. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. The American J Managed Care. 2012;18(13 Suppl):S295-302.
4. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205-2219.
5. Noss EH, Brenner MB. The role and therapeutic implications of fibroblast-like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis. Immunological reviews. 2008;223:252-270.
6. Datta S, Kundu S, Ghosh P, De S, Ghosh A, Chatterjee M. Correlation of oxidant status with oxidative tissue damage in patients with rheumatoid arthritis. Clinical rheumatology. 2014;33(11):1557-1564.
7. Kundu S, Ghosh P, Datta S, Ghosh A, Chattopadhyay S, Chatterjee M. Oxidative stress as a potential biomarker for determining disease activity in patients with rheumatoid arthritis. Free Radic Res. 2012;46(12):1482-1489.
8. Schonthaler HB, Guinea-Viniegra J, Wagner EF. Targeting inflammation by modulating the Jun/AP-1 pathway. Ann Rheum Dis. 2011;70 Suppl 1:i109-112.
9. Okamoto H, Cujec TP, Yamanaka H, Kamatani N. Molecular aspects of rheumatoid arthritis: role of transcription factors. The FEBS journal. 2008;275(18):4463-4470.
10. Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cellular signalling. 2001;13(2):85-94.
11. Zenz R, Eferl R, Scheinecker C, Redlich K, Smolen J, Schonthaler HB, Kenner L, Tschachler E, Wagner EF. Activator protein 1 (Fos/Jun) functions in inflammatory bone and skin disease. Arthritis research & therapy. 2008;10(1):201.
12. Zenz R, Wagner EF. Jun signalling in the epidermis: From developmental defects to psoriasis and skin tumors. The international journal of biochemistry & cell biology. 2006;38(7):1043-1049.
13. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410(6824):37-40.
14. Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiological reviews. 2012;92(2):689-737.
15. Harnett MM, Katz E, Ford CA. Differential signalling during B-cell maturation. Immunology letters. 2005;98(1):33-44.
16. Liu JO. The yins of T cell activation. Science's STKE : signal transduction knowledge environment. 2005;2005(265):re1.
17. Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004;21(4):467-476.
18. Moens U, Kostenko S, Sveinbjornsson B. The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinases (MAPKAPKs) in Inflammation. Genes (Basel). 2013;4(2):101-133.
19. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22(2):153-183.
20. Goodridge HS, Harnett W, Liew FY, Harnett MM. Differential regulation of interleukin-12 p40 and p35 induction via Erk mitogen-activated protein kinase-dependent and -independent mechanisms and the implications for bioactive IL-12 and IL-23 responses. Immunology. 2003;109(3):415-425.
21. Nah SS, Won HJ, Ha E, Kang I, Cho HY, Hur SJ, Lee SH, Baik HH. Epidermal growth factor increases prostaglandin E2 production via ERK1/2 MAPK and NF-kappaB pathway in fibroblast like synoviocytes from patients with rheumatoid arthritis. Rheumatology international. 2010;30(4):443-449.
22. Barchowsky A, Frleta D, Vincenti MP. Integration of the NF-kappaB and mitogen-activated protein kinase/AP-1 pathways at the collagenase-1 promoter: divergence of IL-1 and TNF-dependent signal transduction in rabbit primary synovial fibroblasts. Cytokine. 2000;12(10):1469-1479.
23. Yamamoto A, Fukuda A, Seto H, Miyazaki T, Kadono Y, Sawada Y, Nakamura I, Katagiri H, Asano T, Tanaka Y, Oda H, Nakamura K, Tanaka S. Suppression of arthritic bone destruction by adenovirus-mediated dominant-negative Ras gene transfer to synoviocytes and osteoclasts. Arthritis Rheum. 2003;48(9):2682-2692.
24. Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, Manning AM, Firestein GS. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest. 2001;108(1):73-81.
25. Liacini A, Sylvester J, Qing Li W, Huang W, Dehnade F, Ahmad M, Zafarullah M. Induction of matrix metalloproteinase-13 gene expression by TNF-α is mediated by MAP kinases, AP-1, and NF-κB transcription factors in articular chondrocytes. Exp Cell Res. 2003;288(1):208-217.
26. Liacini A, Sylvester J, Li WQ, Zafarullah M. Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix biology : journal of the International Society for Matrix Biology. 2002;21(3):251-262.
27. Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, Woodgett JR. Phosphorylation of c-jun mediated by MAP kinases. Nature. 1991;353(6345):670-674.
28. Han J, Lee JD, Bibbs L, Ulevitch RJ. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science (New York, NY). 1994;265(5173):808-811.
29. Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372(6508):739-746.
30. Herskowitz I. MAP kinase pathways in yeast: for mating and more. Cell. 1995;80(2):187-197.
31. Duch A, de Nadal E, Posas F. The p38 and Hog1 SAPKs control cell cycle progression in response to environmental stresses. FEBS Lett. 2012;586(18):2925-2931.
32. Malemud CJ. Targeted drug development for arthritis. Future Medicinal Chemistry. 2012;4(6):701-703.
33. Karki R, Igwe OJ. Toll-like receptor 4-mediated nuclear factor kappa B activation is essential for sensing exogenous oxidants to propagate and maintain oxidative/nitrosative cellular stress. PLoS ONE. 2013;8(9):e73840.
34. Alsousi AA, Igwe OJ. Redox-active trace metal-induced release of high mobility group box 1(HMGB1) and inflammatory cytokines in fibroblast-like synovial cells is Toll-like receptor 4 (TLR4) dependent. Biochimica et Biophysica Acta (BBA) - Mol Basis of Dis. 2018(11) 3847-3858.
35. Andersson U, Erlandsson-Harris H. HMGB1 is a potent trigger of arthritis. Journal internal medicine. 2004;255(3):344-350.
36. Kokkola R, Sundberg E, Ulfgren AK, Palmblad K, Li J, Wang H, Ulloa L, Yang H, Yan XJ, Furie R, Chiorazzi N, Tracey KJ, Andersson U, Harris HE. High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovitis. Arthritis Rheum. 2002;46(10):2598-2603.
37. Kokkola R, Li J, Sundberg E, Aveberger AC, Palmblad K, Yang H, Tracey KJ, Andersson U, Harris HE. Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis Rheum. 2003;48(7):2052-2058.
38. Miesel R, Kroger H, Kurpisz M, Weser U. Induction of arthritis in mice and rats by potassium peroxochromate and assessment of disease activity by whole blood chemiluminescence and 99mpertechnetate-imaging. Free Radic Res. 1995;23(3):213-227.
39. Alsousi AA, Igwe OJ. Autophagy protects against redox active trace metal (RATM) – induced cell death in rabbit synovial fibroblasts. Exp Cell Res. 2018; 374 (1):19-28.
40. Gu J, Liu Y, Xie B, Ye P, Huang J, Lu Z. Roles of toll-like receptors: From inflammation to lung cancer progression. Biomedical reports. 2018;8(2):126-132.
41. Liu Y, Li T, Xu Y, Xu E, Zhou M, Wang B, Shen J. Effects of TLR4 gene silencing on the proliferation and apotosis of hepatocarcinoma HEPG2 cells. Oncology letters. 2016;11(5):3054-3060.
42. Ahmed A, Redmond HP, Wang JH. Links between Toll-like receptor 4 and breast cancer. Oncoimmunology. 2013;2(2):e22945.
43. Wang L, Zhu R, Huang Z, Li H, Zhu H. Lipopolysaccharide-induced toll-like receptor 4 signaling in cancer cells promotes cell survival and proliferation in hepatocellular carcinoma. Dig Dis Sci. 2013;58(8):2223-2236.
44. Malemud CJ. Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways. Anti-inflammatory & anti-allergy agents in medicinal chemistry. 2011;10(2):78-84.
45. Malemud CJ. Intracellular Signaling Pathways in Rheumatoid Arthritis. J Clin & Cellular Immunol. 2013;4:160.
46. Youssef P, Roth J, Frosch M, Costello P, Fitzgerald O, Sorg C, Bresnihan B. Expression of myeloid related proteins (MRP) 8 and 14 and the MRP8/14 heterodimer in rheumatoid arthritis synovial membrane. J Rheumatol. 1999;26(12):2523-2528.
47. Han Z, Boyle DL, Aupperle KR, Bennett B, Manning AM, Firestein GS. Jun N-terminal kinase in rheumatoid arthritis. J Pharmacol Exp Ther. 1999;291(1):124-130.
48. Dean JL, Sarsfield SJ, Tsounakou E, Saklatvala J. p38 Mitogen-activated protein kinase stabilizes mRNAs that contain cyclooxygenase-2 and tumor necrosis factor AU-rich elements by inhibiting deadenylation. J Biol Chem. 2003;278(41):39470-39476.
49. Alsousi AA , Siddiqui S, Igwe OJ. Cytokine-mediated Differential Regulation of Cyclooxygenase-2, High Mobility Group Box 1 Protein and Matrix Metalloproteinase-9 Expression in Fibroblast-like Synovial Cells. J Clin & Exp Pharmacol. 2017;7(4).
50. Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell. 2000;103(2):239-252.
51. David JP, Sabapathy K, Hoffmann O, Idarraga MH, Wagner EF. JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms. J Cell Sci. 2002;115(Pt 22):4317-4325.
52. Nishina H, Fischer KD, Radvanyi L, Shahinian A, Hakem R, Rubie EA, Bernstein A, Mak TW, Woodgett JR, Penninger JM. Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3. Nature. 1997;385(6614):350-353.
53. Sabapathy K, Jochum W, Hochedlinger K, Chang L, Karin M, Wagner EF. Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2. Mech Dev. 1999;89(1-2):115-124.
54. Tournier C, Dong C, Turner TK, Jones SN, Flavell RA, Davis RJ. MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes & Development. 2001;15(11):1419-1426.
55. Varfolomeev E, Goncharov T, Maecker H, Zobel K, Komuves LG, Deshayes K, Vucic D. Cellular inhibitors of apoptosis are global regulators of NF-kappaB and MAPK activation by members of the TNF family of receptors. Sci Signal. 2012;5(216):ra22.
56. Thiel MJ, Schaefer CJ, Lesch ME, Mobley JL, Dudley DT, Tecle H, Barrett SD, Schrier DJ, Flory CM. Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms. Arthritis Rheum. 2007;56(10):3347-3357.
57. Tagoe CE, Marjanovic N, Park JY, Chan ES, Abeles AM, Attur M, Abramson SB, Pillinger MH. Annexin-1 mediates TNF-alpha-stimulated matrix metalloproteinase secretion from rheumatoid arthritis synovial fibroblasts. J Immunol. 2008;181(4):2813-2820.
58. Hannemann N, Jordan J, Paul S, Reid S, Baenkler HW, Sonnewald S, Bäuerle T, Vera J, Schett G, Bozec A. The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages. J Immunol. 2017;198(9):3605-3614.
59. Dooley S, Herlitzka I, Hanselmann R, Ermis A, Henn W, Remberger K, Hopf T, Welter C. Constitutive expression of c-fos and c-jun, overexpression of ets-2, and reduced expression of metastasis suppressor gene nm23-H1 in rheumatoid arthritis. Ann Rheum Dis. 1996;55(5):298-304.