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

• Published in: Clinical rheumatology 2021-06, Vol.40 (6), p.2395-2405
• Main Authors: Saeki, Yukihiko, Okita, Yasutaka, Igashira-Oguro, Eri, Udagawa, Chikako, Murata, Atsuko, Tanaka, Takashi, Mukai, Jyunji, Miyazawa, Keiji, Hoshida, Yoshihiko, Ohshima, Shiro
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Arthritis; Arthritis, Rheumatoid - drug therapy; Benzoquinones; Caspase-8; Cell death; Collagen; Cytokines; Enzyme-linked immunosorbent assay; Etanercept; Flow cytometry; Geldanamycin; Humans; Hyperplasia; Inflammation; Inflammation - drug therapy; Lactams, Macrocyclic; Medicine; Medicine & Public Health; Mice; Necroptosis; NF-kappa B; NF-κB protein; Original Article; Rheumatoid arthritis; Rheumatology; Signal transduction; Therapeutic targets; TNF inhibitors; Tumor necrosis factor receptors; Tumor Necrosis Factor-alpha; Tumor necrosis factor-α; Western blotting
• ISSN: 0770-3198; 1434-9949
• DOI: 10.1007/s10067-021-05579-w

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.