Generic placeholder image

Current Drug Research Reviews


ISSN (Print): 2589-9775
ISSN (Online): 2589-9783

Review Article

The Role of Signaling Pathway in the Biological Cause of Rheumatoid Arthritis

Author(s): Rakesh Kumar Chauhan, Pramod Kumar Sharma and Shikha Srivastava*

Volume 13, Issue 2, 2021

Published on: 09 November, 2020

Page: [130 - 139] Pages: 10

DOI: 10.2174/2589977512999201109215004

Price: $65


Rheumatoid arthritis not only affects synovial joints but also many other sites including heart, blood vessels, and skins. It is more common in females than in males. The exact cause of rheumatoid arthritis is not well established, but the hypothesis reported in the literature is that in the development stage of the disease, both genetics and environmental factors can play an inciting role. Along with these factors, the alteration in the normal physiology of enzymatic action acts as a trigger to develop this condition. Numerous signaling pathways in the pathogenesis of Rheumatoid Arthritis involve activation of mitogen-activated protein kinase, kinases Janus family, P-38 Mitogen- Activated Protein Kinase and Nuclear Factor-kappa B. Interleukin-1, is a proinflammatory cytokine that plays an important role in inflammation in RA. These are also associated with an increase in neutrophil, macrophage and lymphocytic chemotaxis, mast cell degranulation, activation, maturation and survival of T-cells and B-cells activated. These signaling pathways also show that p38α downregulation in myeloid cells exacerbates the severity of symptoms of arthritis. Thus, the present review carters about the detail of different signaling pathways and their role in rheumatoid arthritis.

Keywords: Rheumatoid arthritis, interleukin, JAK-STAT, MAP, signaling pathway, P-38 MAPK.

Graphical Abstract
Chen Z, Bozec A, Ramming A, Schett G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat Rev Rheumatol 2019; 15(1): 9-17.
[] [PMID: 30341437]
Low PS. Purdue Research Foundation, assignee. Treatment and diagnosis of macrophage mediated disease. United States patent US20020192157A1 2014.
Tanaka S. Molecular understanding of pharmacological treatment of osteoporosis. EFORT Open Rev 2019; 4(4): 158-64.
[] [PMID: 31057953]
Malemud CJ. Negative regulators of JAK/STAT signaling in rheumatoid arthritis and osteoarthritis. Int J Mol Sci 2017; 18(3): 484.
[] [PMID: 28245561]
Subbannayya T, Variar P, Advani J, et al. An integrated signal transduction network of macrophage migration inhibitory factor. J Cell Commun Signal 2016; 10(2): 165-70.
[] [PMID: 27139435]
Westra J, Limburg PC. Signal transduction pathways in rheumatoid arthritis with emphasis on the p38 mitogen-activated protein kinase (MAPK) pathwaySignal transduction pathways in RA. 2005; pp. 13-27.
Andrade MJ, Van Lonkhuyzen DR, Upton Z, Satyamoorthy K. Unravelling the insulin-like growth factor I-mediated photoprotection of the skin. Cytokine Growth, F. R. 2019.
Emami J, Ansarypour Z. Receptor targeting drug delivery strategies and prospects in the treatment of rheumatoid arthritis. Res Pharm Sci 2019; 14(6): 471-87.
[] [PMID: 32038727]
Umar S, Hedaya O, Singh AK, Ahmed S. Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation. Toxicol Appl Pharmacol 2015; 287(3): 299-305.
[] [PMID: 26134265]
Sun Y, Zhang L, Zhang M, et al. Characterization of three mitogen-activated protein kinases (MAPK) genes reveals involvement of ERK and JNK, not p38 in defense against bacterial infection in Yesso scallop Patinopecten yessoensis. Fish Shellfish Immunol 2016; 54: 507-15.
[] [PMID: 27155450]
Yang F, Cai HH, Feng XE, et al. 5,2′-Dibromo-2,4,5-trihydroxydiphenylmethanone, a novel immunomodulator of T lymphocytes by regulating the CD4+ T cell subset balance via activating the mitogen-activated protein kinase pathway. Int Immunopharmacol 2019; 72: 487-95.
[] [PMID: 31048246]
Mele S, Johnson TK. Receptor tyrosine kinases in development: insights from Drosophila. Int J Mol Sci 2019; 21(1): 188.
[] [PMID: 31888080]
Dolfi F, Garcia-Guzman M, Vuori K. p130Cas in Integrin Signaling. Signaling Through Cell Adhesion Molecules 2019; 30: 81.
Hu L, Zou F, Grandis JR, Johnson DE. The JNK Pathway in Drug Resistance. In: Johnson DE, Ed. Cancer Sensitizing Agents for Chemotherapy, Targeting Cell Survival Pathways to Enhance Response to Chemotherapy. Academic Press 2019; pp. 87-100.
Nadal-Ribelles M, Sole C, Martínez-Cebrian G, Posas F, de Nadal E. Shaping the Transcriptional Landscape through MAPK Signaling. In: Uchiumi F, Ed. Gene Expression and Control. IntechOpen. 2018.
Kazi JU, Rönnstrand L. FMS-like tyrosine kinase 3/FLT3: from basic science to clinical implications. Physiol Rev 2019; 99(3): 1433-66.
[] [PMID: 31066629]
Malemud CJ. The role of the JAK/STAT signal pathway in rheumatoid arthritis. Ther Adv Musculoskelet 2018; 10(5-6): 117-27.
Segond von Banchet G, König C, Patzer J, et al. Long‐lasting activation of the transcription factor CREB in sensory neurons by interleukin‐1β during antigen‐induced arthritis in rats: a mechanism of persistent arthritis pain? Arthritis Rheum 2016; 68(2): 532-41.
[] [PMID: 26473326]
Cronin RJ. The role of p90 ribosomal S6 kinases (RSKs) in Steroid signalling. Doctoral dissertation, University of Essex. 2019; 1-163.
Park SW, Nhieu J, Persaud SD, et al. A new regulatory mechanism for Raf kinase activation, retinoic acid-bound Crabp1. Sci Rep 2019; 9(1): 1-12.
[] [PMID: 30626917]
Arnoux F, Fina F, Lambert N, et al. Newly Identified BRAF mutation in rheumatoid arthritis. Arthritis Rheum 2016; 68(6): 1377-83.
[] [PMID: 26814611]
Dumaz N, Jouenne F, Delyon J, Mourah S, Bensussan A, Lebbé C. Atypical BRAF and NRAS mutations in mucosal melanoma. Cancers (Basel) 2019; 11(8): 1133.
[] [PMID: 31398831]
Muniyappa H, Das KC. Activation of c-Jun N-terminal kinase (JNK) by widely used specific p38 MAPK inhibitors SB202190 and SB203580: a MLK-3-MKK7-dependent mechanism. Cell Signal 2008; 20(4): 675-83.
[] [PMID: 18222647]
Turner NA, Blythe NM. Cardiac fibroblast p38 MAPK: a critical regulator of myocardial remodeling. J Cardiovasc Dev Dis 2019; 6(3): 27.
[] [PMID: 31394846]
Malemud CJ. The role of the JAK/STAT signal pathway in rheumatoid arthritis. Ther Adv Musculoskelet Dis 2018; 10(5-6): 117-27.
[] [PMID: 29942363]
Li Y, Dong Q, Cui Y. Synergistic inhibition of MEK and reciprocal feedback networks for targeted intervention in malignancy. Cancer Biol Med 2019; 16(3): 415-34.
[PMID: 31565475]
Dai WL, Bao YN, Fan JF, et al. Levo-corydalmine attenuates microglia activation and neuropathic pain by suppressing ASK1-p38 MAPK/NF-κB signaling pathways in rat spinal cord. Anesth Pain Med 2020.
Zhou D, Zhang S, Hu L, et al. Inhibition of apoptosis signal-regulating kinase by paeoniflorin attenuates neuroinflammation and ameliorates neuropathic pain. J Neuroinflammation 2019; 16(1): 83.
[] [PMID: 30975172]
Xin P, Xu X, Deng C, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol 2020; 80: 106210.
[] [PMID: 31972425]
Fragoulis GE, McInnes IB, Siebert S. JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology (Oxford) 2019; 58(Suppl. 1): i43-54.
[] [PMID: 30806709]
Waldmann TA, Chen J. Disorders of the JAK/STAT pathway in T cell lymphoma pathogenesis: implications for immunotherapy. Annu Rev Immunol 2017; 35: 533-50.
[] [PMID: 28182501]
Isomäki P, Junttila I, Vidqvist KL, Korpela M, Silvennoinen O. The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels. Rheumatology (Oxford) 2015; 54(6): 1103-13.
[] [PMID: 25406356]
Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 2017; 16(12): 843-62.
[] [PMID: 29104284]
Lin JX, Leonard WJ. Fine-tuning cytokine signals. Annu Rev Immunol 2019; 37(37): 295-324.
[] [PMID: 30649989]
Moshapa FT, Riches-Suman K, Palmer TM. Therapeutic targeting of the proinflammatory IL-6-JAK/STAT signalling pathways responsible for vascular restenosis in type 2 diabetes mellitus. Cardiol Res Pract 2019; 2019: 9846312.
[] [PMID: 30719343]
Rex J, Lutz A, Faletti LE, et al. IL-1β and TNFα differentially influence NF-κB activity and FasL-induced apoptosis in primary murine hepatocytes during LPS-induced inflammation. Front Physiol 2019; 10(10): 117.
[] [PMID: 30842741]
Wang J, Zhao Q. Linc02381 exacerbates rheumatoid arthritis through adsorbing miR-590-5p and activating the mitogen-activated protein kinase signaling pathway in rheumatoid arthritis-fibroblast-like synoviocytes. Cell Transplant 2020; 29 963689720938023
[] [PMID: 32608996]
Li F, Xiao H, Zhou F, Hu Z, Yang B. Study of HSPB6: insights into the properties of the multifunctional protective agent. Cell Physiol Biochem 2017; 44(1): 314-32.
[] [PMID: 29132139]
Yang Y, Kim SC, Yu T, et al. Functional roles of p38 mitogen-activated protein kinase in macrophage-mediated inflammatory responses. Mediators Inflamm 2014; 2014: 352371.
[] [PMID: 24771982]
Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 2007; 1773(8): 1358-75.
[] [PMID: 17481747]
Gupta J, Nebreda AR. Roles of p38α mitogen-activated protein kinase in mouse models of inflammatory diseases and cancer. FEBS J 2015; 282(10): 1841-57.
[] [PMID: 25728574]
Cao YX, Huang D, Liu J, et al. A novel Chinese medicine, Xinfeng capsule, modulates proinflammatory cytokines via regulating the Toll-Like Receptor 4 (TLR4)/Mitogen-Activated Protein Kinase (MAPK)/Nuclear Kappa B (NF-κB) signaling pathway in an adjuvant arthritis rat model. Med Sci Monit 2019; 25: 6767-74.
[] [PMID: 31495827]
Topping L. Targeting microvesicles to the arthritic joint using antibodies specific to damaged cartilage (doctoral dissertation) 2019.
Shraga A, Olshvang E, Davidzohn N, et al. Covalent docking identifies a potent and selective MKK7 inhibitor. Cell Chem Biol 2019; 26(1): 98-108.e5.
[] [PMID: 30449673]
Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002; 298(5600): 1911-2.
[] [PMID: 12471242]
Hsia CH, Velusamy M, Jayakumar T, et al. Mechanisms of TQ-6, a novel ruthenium-derivative compound, against lipopolysaccharide-induced in vitro macrophage activation and liver injury in experimental mice: the crucial role of p38 MAPK and NF-κB signaling. Cells 2018; 7(11): 217.
[] [PMID: 30463239]
Baker RG, Hayden MS, Ghosh S. NF-κB, inflammation, and metabolic disease. Cell Metab 2011; 13(1): 11-22.
[] [PMID: 21195345]
Chapman MA, Sundberg CJ. Exercise, gene regulation, and cardiometabolic disease. In: Kokkinos P, Narayan P, Eds. Cardiorespiratory Fitness in Cardiometabolic Diseases. Cham: Springer 2019; pp. 11-22.
Ter Haar NM, van Dijkhuizen EHP, Swart JF, et al. Treatment to target using recombinant Interleukin-1 receptor antagonist as First-Line monotherapy in New-Onset systemic juvenile idiopathic arthritis: results from a Five-Year Follow-Up study. Arthritis Rheumatol 2019; 71(7): 1163-73.
[] [PMID: 30848528]
Schett G, Dayer JM, Manger B. Interleukin-1 function and role in rheumatic disease. Nat Rev Rheumatol 2016; 12(1): 14-24.
[] [PMID: 26656658]
Gamboa-Cedeño AM, Castillo M, Xiao W, Waldmann TA, Ranuncolo SM. Alternative and canonical NF-kB pathways DNA-binding hierarchies networks define Hodgkin lymphoma and Non-Hodgkin diffuse large B Cell lymphoma respectively. J Cancer Res Clin Oncol 2019; 145(6): 1437-48.
[] [PMID: 30941572]
Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in human disease. Immunol Rev 2008; 223(1): 87-113.
[] [PMID: 18613831]
Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Sig Transduct Target Ther 2017; 2: 17023.
Khandia R, Munjal A. Interplay between inflammation and cancer. Adv Protein Chem Struct Biol 2020; 119: 199-245.
[] [PMID: 31997769]
Hu J, Pezzella F. The signalling pathways in cancer. In: Oxford Textbook of Cancer Biology. 2019; pp. 155-77.
Brahmachari G. Discovery and development of anti-inflammatory agents from natural products: an overview. In: Brahmachari G, Ed. Natural Product Drug Discovery. Elsevier 2019.
Schiff MH. Role of interleukin 1 and interleukin 1 receptor antagonist in the mediation of rheumatoid arthritis. Ann Rheum Dis 2000; 59(59)(Suppl. 1): i103-8.
[] [PMID: 11053099]
Di Benedetto P, Ruscitti P, Vadasz Z, Toubi E, Giacomelli R. Macrophages with regulatory functions, a possible new therapeutic perspective in autoimmune diseases. Autoimmun Rev 2019; 18(10): 102369.
[] [PMID: 31404701]
Sakaguchi S, Benham H, Cope AP, Thomas R. T-cell receptor signaling and the pathogenesis of autoimmune arthritis: insights from mouse and man. Immunol Cell Biol 2012; 90(3): 277-87.
[] [PMID: 22418389]
Huse M. The T-cell-receptor signaling network. J Cell Sci 2009; 122(Pt 9): 1269-73.
[] [PMID: 19386893]
Mellado M, Martínez-Muñoz L, Cascio G, Lucas P, Pablos JL, Rodríguez-Frade JM. T cell migration in rheumatoid arthritis. Front Immunol 2015; 6(6): 384.
[PMID: 26284069]
Arellano B, Graber DJ, Sentman CL. Regulatory T cell-based therapies for autoimmunity. Discov Med 2016; 22(119): 73-80.
[PMID: 27585233]
Malemud CJ. Intracellular signaling pathways in rheumatoid arthritis. J Clin Exp Immunol 2013; 4: 160.
Lu N, Malemud CJ. Extracellular signal-regulated kinase: a regulator of cell growth, inflammation, chondrocyte and bone cell receptor-mediated gene expression. Int J Mol Sci 2019; 20(15): 3792.
[] [PMID: 31382554]
Dong S. Pharmacologic and genetic investigation of PI3K p110delta in chronic lymphocytic Leukemia. Doctoral dissertation, The Ohio State University.
Weichhart T, Säemann MD. The PI3K/Akt/mTOR pathway in innate immune cells: emerging therapeutic applications. Ann Rheum Dis 2008; 67(67)(Suppl. 3): iii70-4.
[] [PMID: 19022819]
Ren F, Zhang HY, Piao ZF, et al. Inhibition of glycogen synthase kinase 3b activity regulates Toll-like receptor 4-mediated liver inflammation. 2012; 20(9): 693-7.
Zhu L, Li C, Liu Q, Xu W, Zhou X. Molecular biomarkers in cardiac hypertrophy. J Cell Mol Med 2019; 23(3): 1671-7.
[] [PMID: 30648807]
Aoto PC, Stanfield RL, Wilson IA, Dyson HJ, Wright PE. A dynamic switch in inactive p38γ leads to an excited state on the pathway to an active kinase. Biochemistry 2019; 58(51): 5160-72.
[] [PMID: 31794659]
Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK–STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs 2017; 77(5): 521-46.
[] [PMID: 28255960]
Ferrer MD, Busquets-Cortés C, Capó X, et al. Cyclooxygenase-2 inhibitors as a therapeutic target in inflammatory diseases. Curr Med Chem 2019; 26(18): 3225-41.
[] [PMID: 29756563]
Nasonov EL, Eliseev MS. Role of interleukin 1 in the development of human diseases. Rheumatology Science and Practice 2016; 54(1): 60-77.
Maddah M, Harsini S, Rezaei A, et al. Association of Interleukin-2, but not Interferon-Gamma, single nucleotide polymorphisms with juvenile idiopathic arthritis. Allergol Immunopathol (Madr) 2016; 44(4): 303-6.
[] [PMID: 27040810]
Deviatkin AA, Vakulenko YA, Akhmadishina LV, et al. Emerging concepts and challenges in rheumatoid arthritis gene therapy. Biomedicines 2020; 8(1): 1-23.
[] [PMID: 31936504]
Dong C, Fu T, Ji J, Li Z, Gu Z. The role of interleukin-4 in rheumatic diseases. Clin Exp Pharmacol Physiol 2018; 45(8): 747-54.
[] [PMID: 29655253]
Ogata A, Kato Y, Higa S, Yoshizaki K. IL-6 inhibitor for the treatment of rheumatoid arthritis: a comprehensive review. Mod Rheumatol 2019; 29(2): 258-67.
[] [PMID: 30427250]
Chen Z, Kim SJ, Chamberlain ND, et al. The novel role of IL-7 ligation to IL-7 receptor in myeloid cells of rheumatoid arthritis and collagen-induced arthritis. J Immunol 2013; 190(10): 5256-66.
[] [PMID: 23606539]
Slavic V, Stankovic A, Kamenov B. The role of interleukin-8 and monocyte chemotactic protein-1 in rheumatoid arthritis. Facta Universitatis 2005; 12(1): 19-22.
Stephens GL, Swerdlow B, Benjamin E, et al. IL-9 is a Th17-derived cytokine that limits pathogenic activity in organ-specific autoimmune disease. Eur J Immunol 2011; 41(4): 952-62.
[] [PMID: 21360526]
Pope RM, Shahrara S. Possible roles of IL-12-family cytokines in rheumatoid arthritis. Nat Rev Rheumatol 2013; 9(4): 252-6.
[] [PMID: 23090510]
Aouinti S, Giudicelli V, Duroux P, Malouche D, Kossida S, Lefranc MP. IMGT/StatClonotype for pairwise evaluation and visualization of NGS IG and TR IMGT clonotype (AA) diversity or expression from IMGT/HighV-QUEST. Front Immunol 2016; 7(7): 339.
[] [PMID: 27667992]
Abramson SB, Yazici Y. Biologics in development for rheumatoid arthritis: relevance to osteoarthritis. Adv Drug Deliv Rev 2006; 58(2): 212-25.
[] [PMID: 16567019]
Sakurai N, Kuroiwa T, Ikeuchi H, et al. Expression of IL-19 and its receptors in RA: potential role for synovial hyperplasia formation. Rheumatology (Oxford) 2008; 47(6): 815-20.
[] [PMID: 18397956]
Nakachi S, Sumitomo S, Tsuchida Y, et al. Interleukin-10-producing LAG3+ regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis. Arthritis Res Ther 2017; 19(1): 97.
[] [PMID: 28511719]
Noack M, Miossec P. Selected cytokine pathways in rheumatoid arthritis. Seminars in immunopathology. Springer: Berlin Heidelberg 2017; 39: pp. (4)365-83.
Hsu YH, Chang MS. IL-20 in rheumatoid arthritis. Drug Discov Today 2017; 22(6): 960-4.
[] [PMID: 26297177]
Woodward EA, Prêle CM, Nicholson SE, Kolesnik TB, Hart PH. The anti-inflammatory effects of interleukin-4 are not mediated by suppressor of cytokine signalling-1 (SOCS1). Immunology 2010; 131(1): 118-27.
[] [PMID: 20406299]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy