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Adenosine inhibits TNFα-induced MMP-3 production in MH7A rheumatoid arthritis synoviocytes via A_2A receptor signaling.

ABSTRACT: Adenosine causes the anti-inflammatory effect of MTX; however, the contributions of synoviocyte adenosine receptors (AdoRs) are unknown, and matrix metalloproteinase 3 (MMP-3) is released by fibroblast-like synoviocytes in response to inflammatory signaling. To understand the mechanism of the clinical observation that the matrix proteinase-3 concentration of patients with rheumatoid arthritis treated successfully with methotrexate does not usually normalize, we investigated the effects of A_2A AdoR activation and inhibition on tumor necrosis factor-alpha (TNFα)-induced MMP-3 release by MH7A human rheumatoid synovial cells. MH7A cells constitutively expressed membrane-associated A_2A AdoRs, and HENECA enhanced intracellular cAMP. Stimulation with TNFα markedly enhanced release of MMP-3 from MH7A cells, whereas HENECA partially and dose-dependently inhibited TNFα-evoked MMP-3 release. Similarly, dbcAMP partially inhibited TNFα-induced MMP-3 release. Pretreatment with ZM241385 reversed the inhibitory effects of HENECA. Further, TNFα induced p38 MAPK and ATF-2 phosphorylation, whereas HENECA suppressed p38 MAPK and ATF-2 phosphorylation. We concluded that adenosine signaling via A_2A AdoRs, adenylyl cyclase, and cAMP reduces TNFα-induced MMP-3 production by interfering with p38 MAPK/ATF-2 activity. Activation of A_2A AdoR signaling alone using HENECA did not reduce TNFα-induced MMP-3 production to the basal levels, which may explain why MTX usually decreases but does not eliminate serum MMP-3.

SUBMITTER: Konishi H

PROVIDER: S-EPMC9001689 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Adenosine inhibits TNFα-induced MMP-3 production in MH7A rheumatoid arthritis synoviocytes via A<sub>2A</sub> receptor signaling.

Konishi Hiroe H Kanou Shun-En SE Yukimatsu Rika R Inui Mizuki M Sato Motoya M Yamamoto Naruto N Nakano Masayoshi M Koshiba Masahiro M

Scientific reports 20220411 1

Adenosine causes the anti-inflammatory effect of MTX; however, the contributions of synoviocyte adenosine receptors (AdoRs) are unknown, and matrix metalloproteinase 3 (MMP-3) is released by fibroblast-like synoviocytes in response to inflammatory signaling. To understand the mechanism of the clinical observation that the matrix proteinase-3 concentration of patients with rheumatoid arthritis treated successfully with methotrexate does not usually normalize, we investigated the effects of A<sub> ...[more]

PMID: 35410356

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Project description:BackgroundFibroblast-like synoviocytes (FLS) have cancer cell-like characteristics, such as abnormal proliferation and resistance to apoptosis, and play a pathogenic role in rheumatoid arthritis (RA). Hyperproliferation of RA-FLS that can be triggered by the activation of interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling destructs cartilage and bone in RA patients. Chrysoeriol is a flavone found in medicinal herbs such as Chrysanthemi Indici Flos (the dried capitulum of Chrysanthemum indicum L.). These herbs are commonly used in treating RA. Chrysoeriol has been shown to exert anti-inflammatory effects and inhibit STAT3 signaling in our previous studies. This study aimed to determine whether chrysoeriol inhibits hyperproliferation of RA-FLS, and whether inhibiting STAT3 signaling is one of the underlying mechanisms.MethodsIL-6/soluble IL-6 receptor (IL-6/sIL-6R)-stimulated RA-FLS were used to evaluate the effects of chrysoeriol. CCK-8 assay and crystal violet staining were used to examine cell proliferation. Annexin V-FITC/PI double staining was used to detect cell apoptosis. Western blotting was employed to determine protein levels.ResultsChrysoeriol suppressed hyperproliferation of, and evoked apoptosis in, IL-6/sIL-6R-stimulated RA-FLS. The apoptotic effect of chrysoeriol was verified by its ability to cleave caspase-3 and caspase-9. Mechanistic studies revealed that chrysoeriol inhibited activation/phosphorylation of Janus kinase 2 (JAK2, Tyr1007/1008) and STAT3 (Tyr705); decreased STAT3 nuclear level and down-regulated protein levels of Bcl-2 and Mcl-1 that are transcriptionally regulated by STAT3. Over-activation of STAT3 significantly diminished anti-proliferative effects of chrysoeriol in IL-6/sIL-6R-stimulated RA-FLS.ConclusionsWe for the first time demonstrated that chrysoeriol suppresses hyperproliferation of RA-FLS, and suppression of JAK2/STAT3 signaling contributes to the underlying mechanisms. This study provides pharmacological and chemical justifications for the traditional use of chrysoeriol-containing herbs in treating RA, and provides a pharmacological basis for developing chrysoeriol into a novel anti-RA agent.

Project description:Fibroblast-like synoviocytes (FLSs) play a major role in the pathogenesis of rheumatoid arthritis (RA) by secreting effector molecules that promote inflammation and joint destruction. How these cells become and remain activated is still elusive. Both genetic and environmental factors probably play a role in transforming FLSs into inflammatory matrix-degrading cells. As bacterial products have been detected in the joint and shown to trigger joint inflammation, this study was undertaken to investigate whether a bacterial ligand of integrin alpha5beta1, protein I/II, could contribute to the aggressive behavior of RA FLSs. Protein I/II is a pathogen-associated molecular pattern (PAMP) isolated from oral streptococci that have been identified in the joints of RA patients. The response of RA and osteoarthritis FLSs to protein I/II was analyzed using human cancer cDNA expression arrays. RT-PCR and pro-MMP-3 (pro-matrix metalloproteinase) assays were then performed to confirm the up-regulation of gene expression. Protein I/II modulated about 6% of all profiled genes. Three of these, those encoding IL-6, leukemia inhibitory factor, and MMP-3, showed a high expression level in all RA FLSs tested, whereas the expression of genes encoding other members of the cytokine or MMP-family was not affected. Furthermore, the up-regulation of MMP-3 gene expression was followed by an increase of pro-MMP-3 release. The expression of interferon regulatory factor 1 and fibroblast growth factor-5 was also up-regulated, although the expression levels were lower. Only one gene, that for insulin-like growth factor binding protein-4, was down-regulated in all RA FLSs. In contrast, in osteoarthritis FLSs only one gene, that for IL-6, was modulated. These results suggest that a bacterial ligand of integrin alpha5beta1 may contribute to the aggressive behavior of RA FLSs by inducing the release of pro-inflammatory cytokines and a cartilage-degrading enzyme, such as IL-6 and MMP-3, respectively.

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Adenosine inhibits TNFα-induced MMP-3 production in MH7A rheumatoid arthritis synoviocytes via A_2A receptor signaling.

Publications

Adenosine inhibits TNFα-induced MMP-3 production in MH7A rheumatoid arthritis synoviocytes via A<sub>2A</sub> receptor signaling.

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Adenosine inhibits TNFα-induced MMP-3 production in MH7A rheumatoid arthritis synoviocytes via A2A receptor signaling.

Publications

Adenosine inhibits TNFα-induced MMP-3 production in MH7A rheumatoid arthritis synoviocytes via A<sub>2A</sub> receptor signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Adenosine inhibits TNFα-induced MMP-3 production in MH7A rheumatoid arthritis synoviocytes via A_2A receptor signaling.