Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Experimental and Therapeutic Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-0981 Online ISSN: 1792-1015
Journal Cover
February-2022 Volume 23 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
February-2022 Volume 23 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms

  • Authors:
    • Jinwan Du
  • View Affiliations / Copyright

    Affiliations: Department of Rheumatology and Immunology, Chongqing Ninth People's Hospital, Beibei, Chongqing 400700, P.R. China
  • Article Number: 141
    |
    Published online on: December 14, 2021
       https://doi.org/10.3892/etm.2021.11064
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

The presence of Bruton's tyrosine kinase (BTK) in macrophages has been recommended as a promising therapeutic target for rheumatoid arthritis (RA). In addition, activated macrophages in the inflamed joints of patients with RA can also produce a plethora of cytokines, such as TNF‑α. The aim of the present study was to investigate the potential role of BTK and TNF‑α in the regulation of RA. The results demonstrated that higher levels of BTK and TNF‑α were observed in macrophages in inflamed RA joints compared with those in normal joint tissues. Subsequently, the role of BTK and TNF‑α in the regulation of cellular process in inflammatory macrophages was analyzed. It was demonstrated that aberrant expression of BTK and TNF‑α in inflammatory macrophages can lead to higher cell proliferation rates. Once the expression of BTK or TNF‑α was restricted by using short interfering (si)RNAs (siBTK or siTNF‑α), the activity of inflammatory macrophages was significantly downregulated. Of note, when the expression of BTK and TNF‑α was simultaneously decreased, the proliferation rate of inflammatory macrophages was inhibited to the greatest extent. Subsequently, the underlying mechanisms through which BTK and TNF‑α can regulate RA were investigated. The results demonstrated that BTK mainly regulated the ERK/JNK pathway, while TNF‑α mainly affected the inactive rhomboid protein 2/B‑cell‑activating factor pathway. Finally, animal experiments demonstrated that simultaneous silencing of both BTK and TNF‑α can significantly alleviate the symptoms associated with RA.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

De Cock D and Hyrich K: Malignancy and rheumatoid arthritis: Epidemiology, risk factors and management. Best Pract Res Clin Rheumatol. 32:869–886. 2018.PubMed/NCBI View Article : Google Scholar

2 

Wasserman AM: Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 84:1245–1252. 2011.PubMed/NCBI

3 

Wasserman A: Rheumatoid arthritis: Common questions about diagnosis and management. Am Fam Physician. 97:455–462. 2018.PubMed/NCBI

4 

McInnes IB and Schett G: The pathogenesis of rheumatoid arthritis. N Engl J Med. 365:2205–2219. 2011.PubMed/NCBI View Article : Google Scholar

5 

Croia C, Bursi R, Sutera D, Petrelli F, Alunno A and Puxeddu I: One year in review 2019: Pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 37:347–357. 2019.PubMed/NCBI

6 

Udalova IA, Mantovani A and Feldmann M: Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol. 12:472–485. 2016.PubMed/NCBI View Article : Google Scholar

7 

Rana AK, Li Y, Dang Q and Yang F: Monocytes in rheumatoid arthritis: Circulating precursors of macrophages and osteoclasts and, their heterogeneity and plasticity role in RA pathogenesis. Int Immunopharmacol. 65:348–359. 2018.PubMed/NCBI View Article : Google Scholar

8 

Huang QQ, Birkett R, Doyle R, Shi B, Roberts EL, Mao Q and Pope RM: The role of macrophages in the response to TNF inhibition in experimental arthritis. J Immunol. 200:130–138. 2018.PubMed/NCBI View Article : Google Scholar

9 

de La Forest Divonne M, Gottenberg JE and Salliot C: Safety of biologic DMARDs in RA patients in real life: A systematic literature review and meta-analyses of biologic registers. Joint Bone Spine. 84:133–140. 2017.PubMed/NCBI View Article : Google Scholar

10 

Massalska M, Maslinski W and Ciechomska M: Small molecule inhibitors in the treatment of rheumatoid arthritis and beyond: Latest updates and potential strategy for fighting COVID-19. Cells. 9(1876)2020.PubMed/NCBI View Article : Google Scholar

11 

Ternant D, Bejan-Angoulvant T, Passot C, Mulleman D and Paintaud G: Clinical pharmacokinetics and pharmacodynamics of monoclonal antibodies approved to treat rheumatoid arthritis. Clin Pharmacokinet. 54:1107–1123. 2015.PubMed/NCBI View Article : Google Scholar

12 

Accortt NA, Bonafede MM, Collier DH, Iles J and Curtis JR: Risk of subsequent infection among patients receiving tumor necrosis factor inhibitors and other disease-modifying antirheumatic drugs. Arthritis Rheumatol. 68:67–76. 2016.PubMed/NCBI View Article : Google Scholar

13 

Lv J, Wu J, He F, Qu Y, Zhang Q and Yu C: Development of Bruton's tyrosine kinase inhibitors for rheumatoid arthritis. Curr Med Chem. 25:5847–5859. 2018.PubMed/NCBI View Article : Google Scholar

14 

Hendriks RW, Yuvaraj S and Kil LP: Targeting Bruton's tyrosine kinase in B cell malignancies. Nat Rev Cancer. 14:219–232. 2014.PubMed/NCBI View Article : Google Scholar

15 

Norman P: Investigational Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs. 25:891–899. 2016.PubMed/NCBI View Article : Google Scholar

16 

Hsu J, Gu Y, Tan SL, Narula S, DeMartino JA and Liao C: Bruton's Tyrosine Kinase mediates platelet receptor-induced generation of microparticles: A potential mechanism for amplification of inflammatory responses in rheumatoid arthritis synovial joints. Immunol Lett. 150:97–104. 2013.PubMed/NCBI View Article : Google Scholar

17 

Whang JA and Chang BY: Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov Today. 19:1200–1204. 2014.PubMed/NCBI View Article : Google Scholar

18 

Di Paolo JA, Huang T, Balazs M, Barbosa J, Barck KH, Bravo BJ, Carano RA, Darrow J, Davies DR, DeForge LE, et al: Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nat Chem Biol. 7:41–50. 2011.PubMed/NCBI View Article : Google Scholar

19 

Wu J, Zhu Z, Yu Q and Ding C: Tyrosine kinase inhibitors for the treatment of rheumatoid arthritis: Phase I to Ⅱ clinical trials. Expert Opin Investig Drugs. 28:1113–1123. 2019.PubMed/NCBI View Article : Google Scholar

20 

Erickson RI, Schutt LK, Tarrant JM, McDowell M, Liu L, Johnson AR, Lewin-Koh SC, Hedehus M, Ross J, Carano RA, et al: Bruton's tyrosine kinase small molecule inhibitors induce a distinct pancreatic toxicity in rats. J Pharmacol Exp Ther. 360:226–238. 2017.PubMed/NCBI View Article : Google Scholar

21 

Gowhari Shabgah A, Shariati-Sarabi Z, Tavakkol-Afshari J, Ghasemi A, Ghoryani M and Mohammadi M: A significant decrease of BAFF, APRIL, and BAFF receptors following mesenchymal stem cell transplantation in patients with refractory rheumatoid arthritis. Gene. 732(144336)2020.PubMed/NCBI View Article : Google Scholar

22 

Li J, Hsu HC and Mountz JD: Managing macrophages in rheumatoid arthritis by reform or removal. Curr Rheumatol Rep. 14:445–454. 2012.PubMed/NCBI View Article : Google Scholar

23 

Moura RA, Quaresma C, Vieira AR, Gonçalves MJ, Polido-Pereira J, Romão VC, Martins N, Canhão H and Fonseca JE: B-cell phenotype and IgD-CD27- memory B cells are affected by TNF-inhibitors and tocilizumab treatment in rheumatoid arthritis. PLoS One. 12(e0182927)2017.PubMed/NCBI View Article : Google Scholar

24 

Schiff M, Combe B, Dörner T, Kremer JM, Huizinga TW, Veenhuizen M, Gill A, Komocsar W, Berclaz PY, Ortmann R, et al: Efficacy and safety of tabalumab, an anti-BAFF monoclonal antibody, in patients with moderate-to-severe rheumatoid arthritis and inadequate response to TNF inhibitors: Results of a randomised, double-blind, placebo-controlled, phase 3 study. RMD Open. 1(e000037)2015.PubMed/NCBI View Article : Google Scholar

25 

Zhao G, Liu A, Zhang Y, Zuo ZQ, Cao ZT, Zhang HB, Xu CF and Wang J: Nanoparticle-delivered siRNA targeting Bruton's tyrosine kinase for rheumatoid arthritis therapy. Biomater Sci. 7:4698–4707. 2019.PubMed/NCBI View Article : Google Scholar

26 

Chang BY, Huang MM, Francesco M, Chen J, Sokolove J, Magadala P, Robinson WH and Buggy JJ: The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells. Arthritis Res Ther. 13(R115)2011.PubMed/NCBI View Article : Google Scholar

27 

Cao Y, Lu G, Chen X, Chen X, Guo N and Li W: BAFF is involved in the pathogenesis of IgA nephropathy by activating the TRAF6/NF-κB signaling pathway in glomerular mesangial cells. Mol Med Rep. 21:795–805. 2020.PubMed/NCBI View Article : Google Scholar

28 

O'Neil LJ and Kaplan MJ: Neutrophils in rheumatoid arthritis: breaking immune tolerance and fueling disease. Trends Mol Med. 25:215–227. 2019.PubMed/NCBI View Article : Google Scholar

29 

Calabresi E, Petrelli F, Bonifacio AF, Puxeddu I and Alunno A: One year in review 2018: Pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 36:175–184. 2018.PubMed/NCBI

30 

Boissier MC, Semerano L, Challal S, Saidenberg-Kermanac'h N and Falgarone G: Rheumatoid arthritis: From autoimmunity to synovitis and joint destruction. J Autoimmun. 39:222–228. 2012.PubMed/NCBI View Article : Google Scholar

31 

Kurowska-Stolarska M and Alivernini S: Synovial tissue macrophages: Friend or foe? RMD Open. 3(e000527)2017.PubMed/NCBI View Article : Google Scholar

32 

Thalhamer T, McGrath MA and Harnett MM: MAPKs and their relevance to arthritis and inflammation. Rheumatology (Oxford). 47:409–414. 2008.PubMed/NCBI View Article : Google Scholar

33 

Schett G, Tohidast-Akrad M, Smolen JS, Schmid BJ, Steiner CW, Bitzan P, Zenz P, Redlich K, Xu Q and Steiner G: Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Arthritis Rheum. 43:2501–2512. 2000.PubMed/NCBI View Article : Google Scholar

34 

Salojin KV, Owusu IB, Millerchip KA, Potter M, Platt KA and Oravecz T: Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. J Immunol. 176:1899–1907. 2006.PubMed/NCBI View Article : Google Scholar

35 

Shabgah AG, Shariati-Sarabi Z, Tavakkol-Afshari J and Mohammadi M: The role of BAFF and APRIL in rheumatoid arthritis. J Cell Physiol. 234:17050–17063. 2019.PubMed/NCBI View Article : Google Scholar

36 

Wei F, Chang Y and Wei W: The role of BAFF in the progression of rheumatoid arthritis. Cytokine. 76:537–544. 2015.PubMed/NCBI View Article : Google Scholar

37 

Lichtenthaler SF: iRHOM2 takes control of rheumatoid arthritis. J Clin Invest. 123:560–562. 2013.PubMed/NCBI View Article : Google Scholar

38 

Siggs OM, Xiao N, Wang Y, Shi H, Tomisato W, Li X, Xia Y and Beutler B: iRhom2 is required for the secretion of mouse TNFα. Blood. 119:5769–5771. 2012.PubMed/NCBI View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Du J: Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms. Exp Ther Med 23: 141, 2022.
APA
Du, J. (2022). Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms. Experimental and Therapeutic Medicine, 23, 141. https://doi.org/10.3892/etm.2021.11064
MLA
Du, J."Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms". Experimental and Therapeutic Medicine 23.2 (2022): 141.
Chicago
Du, J."Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms". Experimental and Therapeutic Medicine 23, no. 2 (2022): 141. https://doi.org/10.3892/etm.2021.11064
Copy and paste a formatted citation
x
Spandidos Publications style
Du J: Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms. Exp Ther Med 23: 141, 2022.
APA
Du, J. (2022). Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms. Experimental and Therapeutic Medicine, 23, 141. https://doi.org/10.3892/etm.2021.11064
MLA
Du, J."Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms". Experimental and Therapeutic Medicine 23.2 (2022): 141.
Chicago
Du, J."Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms". Experimental and Therapeutic Medicine 23, no. 2 (2022): 141. https://doi.org/10.3892/etm.2021.11064
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team