Notch Signaling Mediates TNF-α-induced IL-6 Production in Cultured Fibroblast-like Synoviocytes from Rheumatoid Arthritis

Overview

Journal Clin Dev Immunol

Specialty Allergy & Immunology

Date 2011 Dec 23

PMID 22190977

Citations 29

Authors

Zhijun Jiao

Wenhong Wang

Jie Ma

Shengjun Wang

Zhaoliang Su

Huaxi Xu

Affiliations

Soon will be listed here.

Abstract

It has been reported that Notch family proteins are expressed in synovium tissue and involved in the proliferation of synoviocyte from rheumatoid arthritis (RA). The aim of this paper was to investigate whether Notch signaling mediated TNF-α-induced cytokine production of cultured fibroblast-like synoviocytes (FLSs) from RA. Exposure of RA FLSs to TNF-α (10 ng/ml) led to increase of Hes-1, a target gene of Notch signaling, and a marked upregulation of Notch 2, Delta-like 1, and Delta-like 3 mRNA levels. Blockage of Notch signaling by a γ-secretase inhibitor (DAPT) inhibited IL-6 secretion of RA FLSs in response to TNF-α while treatment with recombinant fusion protein of Notch ligand Delta-like 1 promoted such response. TNF-α stimulation also induced IL-6 secretion in OA FLSs; however, the Hes-1 level remained unaffected. Our data confirm the functional involvement of Notch pathway in the pathophysiology of RA FLSs which may provide a new target for RA therapy.

Citing Articles

Updates on Inflammatory Molecular Pathways Mediated by ADAM17 in Autoimmunity.

Sisto M, Lisi S Cells. 2025; 13(24.

PMID: 39768182 PMC: 11674862. DOI: 10.3390/cells13242092.

Another Notch in the Belt of Rheumatoid Arthritis.

Zack S, Alzoubi O, Satoeya N, Singh K, Deen S, Nijim W Arthritis Rheumatol. 2024; 76(10):1475-1487.

PMID: 38961731 PMC: 11421962. DOI: 10.1002/art.42937.

The Notch signaling-regulated angiogenesis in rheumatoid arthritis: pathogenic mechanisms and therapeutic potentials.

Zhao F, He Y, Zhao Z, He J, Huang H, Ai K Front Immunol. 2023; 14:1272133.

PMID: 38022508 PMC: 10643158. DOI: 10.3389/fimmu.2023.1272133.

Signaling pathways in rheumatoid arthritis: implications for targeted therapy.

Ding Q, Hu W, Wang R, Yang Q, Zhu M, Li M Signal Transduct Target Ther. 2023; 8(1):68.

PMID: 36797236 PMC: 9935929. DOI: 10.1038/s41392-023-01331-9.

Innate and adaptive immune abnormalities underlying autoimmune diseases: the genetic connections.

Chi X, Huang M, Tu H, Zhang B, Lin X, Xu H Sci China Life Sci. 2023; 66(7):1482-1517.

PMID: 36738430 PMC: 9898710. DOI: 10.1007/s11427-021-2187-3.

References

Bartok B, Firestein G . Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010; 233(1):233-55. PMC: 2913689. DOI: 10.1111/j.0105-2896.2009.00859.x. View

Fiuza U, Martinez Arias A . Cell and molecular biology of Notch. J Endocrinol. 2007; 194(3):459-74. DOI: 10.1677/JOE-07-0242. View

McInnes I, Schett G . Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007; 7(6):429-42. DOI: 10.1038/nri2094. View

Klarenbeek N, Kerstens P, Huizinga T, Dijkmans B, Allaart C . Recent advances in the management of rheumatoid arthritis. BMJ. 2010; 341:c6942. DOI: 10.1136/bmj.c6942. View

Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K . Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986; 29(8):1039-49. DOI: 10.1002/art.1780290816. View

Neumann E, Lefevre S, Zimmermann B, Gay S, Muller-Ladner U . Rheumatoid arthritis progression mediated by activated synovial fibroblasts. Trends Mol Med. 2010; 16(10):458-68. DOI: 10.1016/j.molmed.2010.07.004. View

Zhang X, Aubin J, Kim T, Payne U, Chiu B, Inman R . Synovial fibroblasts infected with Salmonella enterica serovar Typhimurium mediate osteoclast differentiation and activation. Infect Immun. 2004; 72(12):7183-9. PMC: 529137. DOI: 10.1128/IAI.72.12.7183-7189.2004. View

Yabe Y, Matsumoto T, Tsurumoto T, Shindo H . Immunohistological localization of Notch receptors and their ligands Delta and Jagged in synovial tissues of rheumatoid arthritis. J Orthop Sci. 2005; 10(6):589-94. DOI: 10.1007/s00776-005-0943-3. View

Jiao Z, Wang W, Guo M, Zhang T, Chen L, Wang Y . Expression analysis of Notch-related molecules in peripheral blood T helper cells of patients with rheumatoid arthritis. Scand J Rheumatol. 2010; 39(1):26-32. DOI: 10.3109/03009740903124424. View

10.

Keerthivasan S, Suleiman R, Lawlor R, Roderick J, Bates T, Minter L . Notch signaling regulates mouse and human Th17 differentiation. J Immunol. 2011; 187(2):692-701. PMC: 3131467. DOI: 10.4049/jimmunol.1003658. View

11.

Scott D, Wolfe F, Huizinga T . Rheumatoid arthritis. Lancet. 2010; 376(9746):1094-108. DOI: 10.1016/S0140-6736(10)60826-4. View

12.

Okamoto T . The epigenetic alteration of synovial cell gene expression in rheumatoid arthritis and the roles of nuclear factor kappaB and Notch signaling pathways. Mod Rheumatol. 2006; 15(2):79-86. DOI: 10.1007/s10165-004-0372-8. View

13.

Artavanis-Tsakonas S, Muskavitch M . Notch: the past, the present, and the future. Curr Top Dev Biol. 2010; 92:1-29. DOI: 10.1016/S0070-2153(10)92001-2. View

14.

Ando K, Kanazawa S, Tetsuka T, Ohta S, Jiang X, Tada T . Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts. Oncogene. 2003; 22(49):7796-803. DOI: 10.1038/sj.onc.1206965. View

15.

Arnett F, Edworthy S, Bloch D, McShane D, Fries J, Cooper N . The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31(3):315-24. DOI: 10.1002/art.1780310302. View

16.

Augelli-Szafran C, Wei H, Lu D, Zhang J, Gu Y, Yang T . Discovery of notch-sparing gamma-secretase inhibitors. Curr Alzheimer Res. 2010; 7(3):207-9. PMC: 2858232. DOI: 10.2174/156720510791050920. View

17.

Fox D, Gizinski A, Morgan R, Lundy S . Cell-cell interactions in rheumatoid arthritis synovium. Rheum Dis Clin North Am. 2010; 36(2):311-23. PMC: 2879397. DOI: 10.1016/j.rdc.2010.02.004. View

18.

Ishii H, Nakazawa M, Yoshino S, Nakamura H, Nishioka K, Nakajima T . Expression of notch homologues in the synovium of rheumatoid arthritis and osteoarthritis patients. Rheumatol Int. 2001; 21(1):10-4. DOI: 10.1007/s002960100119. View

19.

Nakazawa M, Ishii H, Aono H, Takai M, Honda T, ARATANI S . Role of Notch-1 intracellular domain in activation of rheumatoid synoviocytes. Arthritis Rheum. 2001; 44(7):1545-54. DOI: 10.1002/1529-0131(200107)44:7<1545::AID-ART278>3.0.CO;2-Q. View