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Modulation of TNFR 1-triggered two opposing signals for inflammation and apoptosis via RIPK 1 disruption by geldanamycin in rheumatoid arthritis

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Abstract

Objectives

To evaluate the ability of geldanamycin to modulate two opposing TNFα/TNFR1-triggered signals for inflammation and cell death.

Methods

The effects of geldanamycin on TNFα-induced proinflammatory cytokine production, apoptosis, NF-κB activation, caspase activation, and necroptosis in a human rheumatoid synovial cell line (MH7A) were evaluated via ELISA/qPCR, flow cytometry, dual-luciferase reporter assay, and western blotting assay, respectively. In addition, therapeutic effects on murine collagen-induced arthritis (CIA) were also evaluated.

Results

Geldanamycin disrupted RIPK1 in MH7A, thereby inhibiting TNFα-induced proinflammatory cytokine production and enhancing apoptosis. TNFα-induced NF-κB and MLKL activation was inhibited, whereas caspase 8 activation was enhanced. Recombinant RIPK1 restored the geldanamycin-mediated inhibition of TNFα-induced NF-κB activation. In addition, GM showed more clinical effectiveness than a conventional biologic TNF inhibitor, etanercept, in murine CIA and significantly attenuated synovial hyperplasia, a histopathological hallmark of RA.

Conclusions

GM disrupts RIPK1 and selectively inhibits the TNFR1-triggered NF-κB activation signaling pathway, while enhancing the apoptosis signaling pathway upon TNFα stimulation, thereby redressing the balance between these two opposing signals in a human rheumatoid synovial cell line. Therapeutic targeting RIPK1 may be a novel concept which involves TNF inhibitor acting as a TNFR1-signal modulator and have great potential for a more fundamental, effective, and safer TNF inhibitor.

Key Points

• Geldanamycin (GM) disrupts RIPK1 and selectively inhibits the TNFR1-triggered NF-κB activation signaling pathway while enhancing the apoptosis signaling pathway upon TNFα stimulation, thereby redressing the balance between these two opposing signals in a human rheumatoid synovial cell line, MH7A.

• GM showed more clinical effectiveness than a conventional biologic TNF-inhibitor, etanercept, in murine collagen-induced arthritis (CIA), and significantly attenuated synovial hyperplasia, a histopathological hallmark of RA.

• Therapeutic targeting RIPK1 may be a novel concept which involves TNF inhibitor acting as a TNFR1-signal modulator and have great potential for a more fundamental, effective, and safer TNF-inhibitor.

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Data availability

All data and materials are available with permission of the authors.

Abbreviations

RIPK1:

Receptor-interacting serine/threonine-protein kinase 1

GM:

Geldanamycin

TNF:

Tumor necrosis factor

TNFR:

TNFα receptor

TNFi:

TNF-inhibitor

IL-1β:

Interleukin-1beta

IL-6:

Interleukin-6

ELISA:

Enzyme-linked immunosorbent assay

qPCR:

Quantitative real-time polymerase chain reaction

RA:

Rheumatoid arthritis

FLS:

Fibroblast-like synovial cells

NF-κB:

Nuclear factor-kappa B

HSP:

Heat shock protein

MLKL:

Mixed lineage kinase domain-like

CIA:

Collagen-induced arthritis

ETN:

Etanercept

JNK:

c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular signal-regulated kinase

References

  1. Feldmann M, Brennan FM, Foxwell BM, Maini RN (2001) The role of TNF alpha and IL-1 in rheumatoid arthritis. Curr Dir Autoimmun 3:188–199

    Article  CAS  Google Scholar 

  2. Scott DL (2012) Biologics-based therapy for the treatment of rheumatoid arthritis. Clin Pharmacol Ther 91:30–43

    Article  CAS  Google Scholar 

  3. Caporali R, Crepaldi G, Codullo V, Benaglio F, Monti S, Todoerti M et al (2018) 20 years of experience with tumor necrosis factor inhibitors: what have we learned? Rheumatology 57:vii5–vi10

    Article  CAS  Google Scholar 

  4. Ramos-Casals M, Brito-Zeron P, Munoz S, Soria N, Galiana G, Bertolaccini L et al (2007) Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine. 86:242–245

    Article  Google Scholar 

  5. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 295:2275–2285

    Article  CAS  Google Scholar 

  6. Chung ES (2003) Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial. Circulation. 107:3133–3140

    Article  CAS  Google Scholar 

  7. Silva-Fernandez L, Hyrich K (2014) Rheumatoid arthritis: when TNF inhibitors fail in RA – weighing up the options. Nat Rev Rheumatol 10:262–264

    Article  CAS  Google Scholar 

  8. Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10:45–65

    Article  CAS  Google Scholar 

  9. Vandenabeele P, Declercq W, Beyaert R, Fiers W (1995) Two tumor necrosis factor receptors: structure and function. Trends Cell Biol 5:392–399

    Article  CAS  Google Scholar 

  10. Wajant H, Scheurich P (2011) TNFR1-induced activation of the classical NF-κB pathway. FEBS J 278:862–876

    Article  CAS  Google Scholar 

  11. Micheau O, Tschopp J (2003) Induction of TNF receptor I mediated apoptosis via two sequential signaling complexes. Cell 114:181–190

    Article  CAS  Google Scholar 

  12. Liu H, Pope RM (2003) The role of apoptosis in rheumatoid arthritis. Curr Opin Pharmacol 3:317–322

    Article  Google Scholar 

  13. Ceponis A, Hietanen J, Tamulaitiene M, Partsch G, Patiala H, Konttinen YT (1999) A comparative quantitative morphometric study of cell apoptosis in synovial membranes in psoriatic, reactive, and rheumatoid arthritis. Rheumatology. 38:431–440

    Article  CAS  Google Scholar 

  14. Bartok B, Firestein GS (2010) Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 233:233–255

    Article  CAS  Google Scholar 

  15. Firestein GS (2009) Etiology and pathogenesis of rheumatoid arthritis. In: Firestein GS, Budd RC, Harris T, IB MI, Ruddy S, Sergent JS (eds) Elsevier 2009Kelly’s Textbook of Rheumatology, vol 8, pp 1035–1086

    Chapter  Google Scholar 

  16. Hsu H, Huang J, Shu H-B, Shu H-B, Baichwal V, Goeddel DV (1996) TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4:387–396

    Article  CAS  Google Scholar 

  17. Cuchet-Lourenco D, Eletto D, Wu C, Plagnol V, Papapietro O, Curtis J et al (2018) Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science 361:810–813

    Article  CAS  Google Scholar 

  18. Dannappel M, Vlantis K, Kumari S, Polykratis A, Kim C, Wachsmuth L, Eftychi C, Lin J, Corona T, Hermance N, Zelic M, Kirsch P, Basic M, Bleich A, Kelliher M, Pasparakis M (2014) RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513:90–94

    Article  CAS  Google Scholar 

  19. Takahashi N, Vereecke L, Bertrand L, Duprez L, Berger SB, Divert T et al (2014) RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis. Nature 4(513):95–99

    Article  Google Scholar 

  20. Schulle TW, Akinaga S, Soga S, Sullivan W, Stensgard B, Toft D et al (1988) Antibiotic radicicol to N-terminal domain of Hsp90 and shares important biologic activities with geldanamaycin. Cell Stress Chaperones 3:100–108

    Article  Google Scholar 

  21. Lewis J, Devin A, Miller A, Lin Y, Rodriguez Y, Neckers L, Liu ZG (2000) Disruption of Hsp90 function results in degradation of the death domain kinase, receptor-interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-κB activation. J Biol Chem 275:10519–10526

    Article  CAS  Google Scholar 

  22. Ting AT, Pimentel-Muinos FX, Seed B (1996) RIP mediates tumor necrosis factor receptor 1 activation of NF-κB but Fas/APO-1-initiated apoptosis. EMBO J 15:6189–6196

    Article  CAS  Google Scholar 

  23. Miyazawa K, Mori A, Okudaira H (1998) Establishment and characterization of a novel human rheumatoid fibroblast-like synoviocyte line, MH7A, immortalized with SV40 T antigen. J Biochem 124:1153–1162

    Article  CAS  Google Scholar 

  24. Zhou W, Yuan J (2014) Necroptosis in health and diseases. Semin Cell Dev Biol 35:14–23

    Article  Google Scholar 

  25. Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X (2012) Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148:213–227

    Article  CAS  Google Scholar 

  26. Williams R, Feldmann M, Maini RN (1992) Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci U S A 89:9784–9788

    Article  CAS  Google Scholar 

  27. Sasai M, Saeki Y, Ohshima S, Nishioka K, Mima T, Tanaka T, Katada Y, Yoshizaki K, Suemura M, Kishimoto T (1999) Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice. Arthritis Rheumatol 42:1635–1643

    Article  CAS  Google Scholar 

  28. Nii T, Kuzuya K, Kabata D, Matsui T, Murata A, Ohya T et al (2019) Crosstalk between tumor necrosis factor-alpha signaling and aryl hydrocarbon receptor signaling in nuclear factor-kappa B activation: a possible molecular mechanism underlying the reduced efficacy of TNF-inhibitors in rheumatoid arthritis by smoking: a possible molecular mechanism underlying the reduced efficacy of TNF-inhibitors in rheumatoid arthritis by smoking. J Autoimmn 98:95–102

    Article  CAS  Google Scholar 

  29. Mori L, Iselin S, De Libero G, Lesslauer W (1996) Attenuation of collagen-induced arthritis in 55-kDa TNF receptor type 1 (TNFR1)-IgG1-treated and TNFR1-deficient mice. J Immunol 57:3178–3182

    Google Scholar 

  30. Simmonds RE, Foxwell BM (2008) Signalling, inflammation and arthritis: NF-κB and its relevance to arthritis and inflammation. Rheumatology. 47:584–590

    Article  CAS  Google Scholar 

  31. Asahara H, Asanuma M, Ogawa N, Nishibayashi S, Inoue H (1995) High DNA-binding activity of transcription factor NF-κB in synovial membranes of patients with rheumatoid arthritis. Biochem Mol Biol Int 37:827–833

    CAS  PubMed  Google Scholar 

  32. Linkermann A, Green DR (2014) Necroptosis. N Engl J Med 370:455–465

    Article  CAS  Google Scholar 

  33. Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P (2014) Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol 15:135–147

    Article  Google Scholar 

  34. Supko JG, Hickman RL, Grever MR, Malspeis L (1995) Preclinical pharmacological evaluation of geldanamycin as an anti-tumor agent. Cancer Chemother Pharmacol 36:305–315

    Article  CAS  Google Scholar 

  35. Russo CD, Polak PE, Mercado PR, Spagnolo A, Sharp A, Murphy P, Kamal A, Burrows FJ, Fritz LC, Feinstein DL (2006) The heat-shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin suppresses glial inflammatory responses and ameliorates experimental autoimmune encephalomyelitis. J Neurochem 99:1351–1362

    Article  CAS  Google Scholar 

  36. Chen Y, Zhu J, Zhu F, Dai BB, Song SJ, Wang ZQ et al (2018) Necrostatin-1 ameliorates adjuvant arthritis rat articular chondrocyte injury via inhibiting ASIC1a-mediated necroptosis. Biochem Biophys Res Commun 504:843–850

    Article  CAS  Google Scholar 

  37. Jhun J, Lee SH, Kim S-Y, Ryu J, Kwon JY, Na HS et al (2019) Min. RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis. J Trans Med 17:84. https://doi.org/10.1186/s12967-019-1809-3

    Article  Google Scholar 

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Acknowledgments

We would like to thank Mitsubishi-Tanabe Pharmaceutical Co., Ltd. for discussions, KAC Co., Ltd. for helping mouse experiments, and Editage (www.editage.jp) for English language editing. We use MH7A cells with the MTA from KISSEI Pharmaceutical CO., Ltd..

Funding

This study was supported partly by the grant from Japan National Hospital Organization (H28-NHO (Immunological disorder diseases)-02).

Author information

Authors and Affiliations

  1. Rheumatology & Allergology, NHO Osaka Minami Medical Center, Kidohigashi-machi, Kawachinagano, Osaka, 586-8521, Japan

    Yukihiko Saeki, Yasutaka Okita, Eri Igashira-Oguro & Shiro Ohshima

  2. Department of Clinical Research, NHO Osaka Minami Medical Center, 2-1 Kidohigashi-machi, Kawachinagano, Osaka, 586-8521, Japan

    Yukihiko Saeki, Chikako Udagawa, Atsuko Murata & Shiro Ohshima

  3. Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Yamada-oka, Suita, Osaka, 565-0871, Japan

    Yasutaka Okita & Eri Igashira-Oguro

  4. Molecular Chemistry, Faculty of Pharmacology, Osaka Ohtani University, Nishikiori-kita, Tondabayashi, Osaka, 584-8540, Japan

    Chikako Udagawa & Takashi Tanaka

  5. Department of Pharmacy, Izumi-City General Hospital, Wake-Cho, Izumi City, Osaka, 594-0072, Japan

    Jyunji Mukai

  6. KISSEI Pharmaceutical CO., L.T.D, Yoshino, Matsumoto City, Nagano Prefecture, 399-8710, Japan

    Keiji Miyazawa

  7. Pathology, NHO Osaka Minami Medical Center, Kidohigashi-machi, Kawachinagano, Osaka, 586-8521, Japan

    Yoshihiko Hoshida

Authors
  1. Yukihiko Saeki
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  2. Yasutaka Okita
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  6. Takashi Tanaka
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  7. Jyunji Mukai
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  8. Keiji Miyazawa
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  9. Yoshihiko Hoshida
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  10. Shiro Ohshima
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Contributions

Y.O., E.O., C.U., and A. M. performed key experiments and analyzed the data. T.T., Y.H., and SO performed or contributed to specific experiments. J.M. performed statistical analysis. Y.S. conceptualized the study, designed and supervised the experiments, analyzed data, and wrote the manuscript.

Corresponding author

Correspondence to Yukihiko Saeki.

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This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. All animal experimental procedures were performed in KAC Co. Ltd. Japan with the approval of the KAC Institutional Animal Care and Use Committee (No.18-1021) and the Animal Research Ethics Committee of the NHO Osaka Minami Medical Center in accordance with the Institutional Guide for the Care and Use of Laboratory Animals.

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Saeki, Y., Okita, Y., Igashira-Oguro, E. et al. Modulation of TNFR 1-triggered two opposing signals for inflammation and apoptosis via RIPK 1 disruption by geldanamycin in rheumatoid arthritis. Clin Rheumatol 40, 2395–2405 (2021). https://doi.org/10.1007/s10067-021-05579-w

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  • DOI: https://doi.org/10.1007/s10067-021-05579-w

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