scholarly journals Adenosine Inhibits TNFα-Induced MMP-3 Production in MH7A RA Synoviocytes via A2A Receptor Signaling

2021 ◽  
Author(s):  
Hiroe Konishi ◽  
Shun-En Kanou ◽  
Rika Yukimatsu ◽  
Mizuki Inui ◽  
Motoya Sato ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Intracellular Camp ◽  
Inhibitory Effects ◽  
Necrosis Factor Alpha ◽  
Matrix Metalloproteinase 3 ◽  
A2a Receptor ◽  
Therapeutic Mechanisms ◽  
Factor Alpha ◽  
Necrosis Factor ◽  
Fibroblast Like Synoviocytes

Abstract Adenosine is the effector molecule; 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 elucidate the therapeutic mechanisms of methotrexate, we investigated the effects of A2A AdoR activation and inhibition on tumor necrosis factor-alpha (TNFa)-induced MMP-3 release by MH7A human rheumatoid synovial cells. MH7A cells constitutively expressed membrane-associated A2A AdoRs, and HENECA enhanced intracellular cAMP. Stimulation with TNFa markedly enhanced release of MMP-3 from MH7A cells, whereas HENECA partially and dose-dependently inhibited TNFa-evoked MMP-3 release. Similarly, dbcAMP partially inhibited TNFa-induced MMP-3 release. Pretreatment with ZM241385 reversed the inhibitory effects of HENECA. Further, TNFa induced p38 MAPK and ATF-2 phosphorylation, whereas HENECA suppressed p38 MAPK and ATF-2 phosphorylation. We concluded that adenosine signaling via A2A AdoRs, adenylyl cyclase, and cAMP reduces TNFa-induced MMP-3 production by interfering with p38 MAPK/ATF-2 activity. Activation of A2A AdoR pathway and suppression of MMP-3 release may explain the antirheumatic effects of methotrexate.

scholarly journals Adenosine inhibits TNFα-induced MMP-3 Production in MH7A RA Synoviocytes via A2A Receptor Signaling

2021 ◽  
Author(s):  
Hiroe Konishi ◽  
Shun-En Kanou ◽  
Rika Yukimatsu ◽  
Mizuki Inui ◽  
Motoya Sato ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Intracellular Camp ◽  
Signaling Proteins ◽  
Necrosis Factor Alpha ◽  
Matrix Metalloproteinase 3 ◽  
A2a Receptor ◽  
Therapeutic Mechanisms ◽  
Factor Alpha

Abstract BackgroundAdenosine is the effector molecule mediating the antirheumatic effects of methotrexate, but the contributions of synoviocyte adenosine receptors (AdoRs) are unknown. Matrix metalloproteinase 3 (MMP-3) is released by fibroblast-like synoviocytes in response to inflammatory signaling, and serum MMP-3 is elevated during active rheumatoid arthritis. To elucidate the therapeutic mechanisms of methotrexate, we investigated the effects of A2A AdoR activation and inhibition on tumor necrosis factor-alpha (TNFa)-induced MMP-3 release by MH7A human rheumatoid synovial cells.MethodsCultured MH7A cells were treated with 25 pg/ml TNFa or vehicle for 24 h in the presence or absence of the selective A2A AdoR agonist HENECA (10, 50, or 100 nM), and MMP-3 release was measured in the culture supernatant. In other experiments, cells were treated with TNFa plus the cAMP analog dbcAMP or pretreated with the A2A AdoR antagonist ZM241385 prior to TNFa with or without HENECA. Activation of the p38 MAPK signaling pathway was evaluated by western blotting of phosphorylated signaling proteins. Treatment group means were compared by independent samples t-tests.ResultsMH7A cells constitutively expressed membrane-associated A2A AdoRs, and HENECA enhanced intracellular cAMP, indicating that these receptors are functionally coupled to adenylyl cyclase. Stimulation with TNFa markedly enhanced release of MMP-3 from MH7A cells, whereas HENECA partially and dose-dependently inhibited TNFa-evoked MMP-3 release. Similarly, dbcAMP partially inhibited TNFa-induced MMP-3 release. Pretreatment with ZM241385 reversed the inhibitory effects of HENECA. Further, TNFa induced p38 MAPK and ATF-2 phosphorylation, whereas HENECA suppressed p38 MAPK and ATF-2 phosphorylation.ConclusionsAdenosine signaling via A2A AdoRs, adenylyl cyclase, and cAMP reduces (although does not completely block) TNFa-induced MMP-3 production, by interfering with p38 MAPK/ATF-2 activity. Activation of A2A AdoR pathway and suppression of MMP-3 release may explain the antirheumatic effects of methotrexate.

scholarly journals Potentiation of early hematopoiesis by tumor necrosis factor-alpha is followed by inhibition of granulopoietic differentiation and proliferation

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 635-644 ◽  
Author(s):  
C Caux ◽  
C Favre ◽  
S Saeland ◽  
V Duvert ◽  
I Durand ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Inhibitory Effects ◽  
Granulocytic Differentiation ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Differentiation And Proliferation ◽  
Necrosis Factor

We have previously shown that tumor necrosis factor-alpha (TNF alpha) strongly potentiates interleukin-3 (IL-3)-induced short-term proliferation of human CD34+ hematopoietic progenitor cells (HPC). Using longer term cultures of CD34+ HPC, we demonstrate here that this initial potentiation ceases after 10 to 12 days; whereupon TNF alpha displays inhibitory effects. Thus, TNF alpha was found to inhibit cells of granulocytic affiliation while it potentiates the development of maturing cells of the monocytic lineage both in liquid and semi-solid (day 14 colony-forming unit) cultures. TNF alpha was demonstrated to reversibly block granulocytic differentiation at the level of uncommitted CD13-, CD15- blast cells that accumulate in IL-3 + TNF alpha cultures. Furthermore, growth of committed granulocytes (CD15+) from IL-3 cultures was also inhibited by TNF alpha through an arrest of cell cycle in G0/G1. Finally, the use of neutralizing anti-TNF alpha monoclonal antibody and limiting dilution studies indicate that the inhibitory effects of TNF alpha are direct. Taken together, our data demonstrate that, following a phase of potentiation of proliferation of early HPC, TNF alpha displays direct inhibitory effects due to negative interference with both granulocytic differentiation and proliferation of granulocytic cells.

Inhibitory effects of tumor necrosis factor alpha on fracture healing in rats

Bone ◽  
1989 ◽  
Vol 10 (6) ◽  
pp. 453-457 ◽  
Author(s):  
J. Hashimoto ◽  
H. Yoshikawa ◽  
K. Takaoka ◽  
N. Shimizu ◽  
K. Masuhara ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Fracture Healing ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Inhibitory Effects ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor
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