Tumour necrosis factor α augments the inhibitory effects of CTLA-4-Ig on osteoclast generation from human monocytes via induction of CD80 expression

Oi, Katsuhiro; Tokunaga, Tadahiro; Kuranobu, Tatsuomi; Yukawa, Kazutoshi; Kohno, Hiroki; Yoshida, Yusuke; Mokuda, Sho; Hirata, Shintaro; Sugiyama, Eiji

doi:10.1111/cei.13271

Cited by 12 publications

(17 citation statements)

References 20 publications

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“…And osteoblasts are the important functional cells for bone formation, which is involved in early osteogenesis and late bone reconstruction (3). Lipopolysaccharide (LPS) produced by dead bacteria and its inducing inflammatory cytokines (4), such as tumor necrosis factor-a (TNF-a) and interleukin-1 play a significant role in alveolar bone resorption, and they can increase osteoclasts production and promote osteoblast apoptosis (5,6). Studies have shown that LPS could affect the proliferation and apoptosis of osteoblasts through multiple signaling pathways transductions, such as the induction of proliferation through Notch pathway, the inhibition of apoptosis through JNK signaling pathway (7,8).…”

Section: Introductionmentioning

confidence: 99%

Antibacterial peptides inhibit MC3T3-E1 cells apoptosis induced by TNF-α through p38 MAPK pathway

Lü

Huan

Liu³

et al. 2020

Ann Transl Med

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Background: Antimicrobial peptides (AMP), as a small molecular polypeptide with a broad antibacterial spectrum and high efficiency, have attracted more and more attention. Few pieces of research on the effect of the antimicrobial peptide on osteoblast under inflammatory conditions have so far been reported. The main aim of this work was to investigate the antiapoptosis effect of the antimicrobial peptide on MC3T3-E1 cells induced by TNF-α and its related mechanism.Methods: Rat MC3T3-E1 cells were co-cultured with different concentrations of antibacterial peptide DP7 and TNF-α.MTS assay, cell scratch test, alkaline phosphatase activity, and alizarin red staining assay were used to determine osteoblast viability in this experiment. Annexin V-FITC/PI double staining cells and flow cytometry were used to analyze apoptosis and Western blot assay detection to show mitogen-activated protein kinase (MAPK) protein expression in rat MC3T3-E1 cells. Then, Realtime polymerase chain reaction (PCR) was used to examine the caspase-3 gene expression. Also, ELISA detection was used to clarify the anti-apoptotic effect of the p38 MAPK inhibitor, SB203580, on cells' apoptosis.Results: Antimicrobial peptide could promote the proliferation, migration, and osteogenic ability of MC3T3-E1 cells induced by TNF-α, but inhibit cell apoptosis rate (P<0.05), and the effect was concentration-dependent. Western blot results showed after TNF-αtreatment, the expression of p-p38 MAPK in the MC3T3-E1 cells increased after TNF-α and antimicrobial peptide cotreatment, TNF-α induced p-p38 MAPK phosphorylation was inhibited, and the difference was statistically significant (P<0.05).Realtime PCR results showed that the gene expression of caspase-3 mRNA was up-regulated after TNF-α treatment, while their expression was down-regulated after cultured with TNF-α and antimicrobial peptide.Elisa's analysis showed that cell apoptosis increased after TNF-α treatment alone, and cell apoptosis was reduced to the normal levels when combined with antimicrobial peptide, and cell apoptosis induced by TNF-α was partially abolished when combined with SB203580.Conclusions: Antimicrobial peptide DP7 could inhibit MC3T3-E1 cells apoptosis induced by TNF-α, and the effect was concentration-dependent. The antiapoptosis activation of the antimicrobial peptide on MC3TE-E1 cells may be related to the inhibition of the p38 MAPK pathway.

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Section: Introductionmentioning

confidence: 99%

Antibacterial peptides inhibit MC3T3-E1 cells apoptosis induced by TNF-α through p38 MAPK pathway

Lü

Huan

Liu³

et al. 2020

Ann Transl Med

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“…On the other hand, it has been recently reported that abatacept exerts a pharmacologic effect directly on monocytes/macrophages and osteoclasts via CD80/86 in a T cell-independent manner [ 10 ]. For example, abatacept directly inhibits osteoclastogenesis by suppressing the differentiation of circulating osteoclast precursors into functional osteoclasts, and this process is mediated by receptor activator of NF-κB ligand expressed by osteoblasts or activated T cells [ 12 , 13 ]. In addition, short-term coculture of synovial macrophages derived from RA patients and Jurkat cells showed that abatacept suppressed in vitro production of inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Abatacept downregulates Fcγ receptor I on circulating monocytes: a potential therapeutic mechanism in patients with rheumatoid arthritis

et al. 2022

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Background Abatacept is a recombinant fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte antigen 4 and the Fc portion of immunoglobulin (Ig) G. The mechanism of action of abatacept in rheumatoid arthritis (RA) is believed to be competitive inhibition of T cell costimulation mediated by the binding of CD28 to CD80/CD86 on antigen-presenting cells, and recent studies have shown that abatacept induces reverse signaling in macrophages and osteoclast precursors in a T cell-independent manner. This study aimed to investigate the therapeutic effects of abatacept on circulating monocytes that contribute to RA pathogenesis. Methods Purified circulating monocytes derived from RA patients and controls were cultured in the absence or presence of abatacept or CD28-Ig for 24 h. The recovered cells were subjected to flow cytometry to evaluate the expression levels of cell surface molecules, and cytokines and chemokines in the culture supernatant were measured by multiplex bead arrays. The expression of candidate molecules was further examined by immunoblotting using total cellular extracts of the cultured monocytes. Finally, the effects of abatacept on cytokine production in monocytes stimulated with the immune complex of anti-citrullinated peptide antibodies (ACPAs) were examined. Results CD64/FcγRI was identified as a monocyte-derived molecule that was downregulated by abatacept but not CD28-Ig. This effect was observed in both RA patients and controls. The abatacept-induced downregulation of CD64/FcγRI was abolished by treatment with anti-CD86 antibodies but not anti-CD80 antibodies. Abatacept suppressed the production of interleukin (IL)-1β, IL-6, C-C motif chemokine ligand 2, and tumor necrosis factor-α in cultured monocytes stimulated with the ACPA immune complex. Conclusions The therapeutic effects of abatacept on RA are mediated, in part, by the downregulation of CD64/FcγRI on circulating monocytes via direct binding to CD86 and the suppression of immune complex-mediated inflammatory cytokine production.

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“…The Fc region of CTLA-4-Ig has been modified to reduce its potential to induce complement-dependent and antibody-dependent cellular cytotoxicity 5 . CTLA-4-Ig treatment has several biological functions, including the suppression of monocyte migration 6 and the inhibition of osteoclast differentiation 7 . Persistently activated autoreactive memory B cells have been associated with the development of RA 8 .…”

Section: Introductionmentioning

confidence: 99%

CTLA-4-Ig internalizes CD80 in fibroblast-like synoviocytes from chronic inflammatory arthritis mouse model

Miura

Isogai

Maeda

et al. 2022

Sci Rep

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CD80 interact with CD28 and CTLA-4 on antigen-presenting cells, and function in the co-stimulatory signaling that regulates T cell activity. CTLA-4-Ig is used to treat RA by blocking co-stimulatory signaling. Chronic inflammatory arthritis was induced in D1BC mice using low-dose arthritogenic antigens and treated with CTLA-4-Ig. We performed histopathology of the joints and lymph nodes, serological examination for rheumatoid factors, and flow cytometric analysis of isolated synovial cells, including CD45− FLSs and CD45+ synovial macrophages. CTLA-4-Ig treatment ameliorated the chronic inflammatory polyarthritis. There was a decrease in the number of infiltrating lymphoid cells in the joints as well as in the levels of RF-IgG associated with a decrease in the number of B cells in the lymph nodes; more than 15% of CD45− FLSs expressed CD80, and a small number of them expressed PD-L1, indicating the presence of PD-L1/CD80 cis-heterodimers in these cells. CTLA-4-Ig internalized CD80, but not PD-L1, in isolated synovial cells. Gene ontology analysis revealed that CTLA-4-Ig internalization did not significantly alter the expression of inflammation-related genes. The therapeutic effect of CTLA-4-Ig appears to extend beyond the lymph nodes into the inflamed synovial compartment through the synergistic inactivation of T cells by the CD80 and PD-L1 axes.

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Tumour necrosis factor α augments the inhibitory effects of CTLA-4-Ig on osteoclast generation from human monocytes via induction of CD80 expression

Cited by 12 publications

References 20 publications

Antibacterial peptides inhibit MC3T3-E1 cells apoptosis induced by TNF-α through p38 MAPK pathway

Antibacterial peptides inhibit MC3T3-E1 cells apoptosis induced by TNF-α through p38 MAPK pathway

Abatacept downregulates Fcγ receptor I on circulating monocytes: a potential therapeutic mechanism in patients with rheumatoid arthritis

CTLA-4-Ig internalizes CD80 in fibroblast-like synoviocytes from chronic inflammatory arthritis mouse model

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