Hypoxia suppresses the production of MMP-9 by human monocyte-derived dendritic cells and requires activation of adenosine receptor A2b via cAMP/PKA signaling pathway.
The migration of dendritic cells (DCs) from the site of antigen-encounter to regional lymphoid organs is crucial for DCs to function as potent antigen-presenting cells. Matrix metalloproteinase-9 (MMP-9) is critically for DCs migration across extracellular matrix (ECM). We verified in previous studies that hypoxia diminished the production of MMP-9 in human monocyte-derived DCs via an unknown mechanism. In this study, we found, for the first time to our knowledge, that hypoxia altered the expression of adenosine receptors on matured DCs (mDCs) toward the predominant expression of adenosine receptor A(2b). MRS1754 (an A(2b)-receptor specific antagonist) was able to counteract the inhibition of hypoxia on MMP-9 by mDCs. We also found that forskolin (a direct adenylate cyclase activator) can mimic the action of hypoxia on the production of MMP-9 by DCs, whereas the adenylate cyclase inhibitor SQ22536 and the PKA inhibitor H89 can abrogate the inhibition of MMP-9 produce by mDCs under hypoxia. The results herein provide initial evidence that the inhibitory effect of hypoxia on MMP-9 by mDCs requires the activation of A(2b) in a cAMP/PKA-dependent pathway. These data offer new insights into our understanding of the molecular mechanisms underlying the migratory function of DCs in local-tissue hypoxic microenvironments.
Zhao
Peng
P
Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan 250012, PR China.
Li
Xin-gang
XG
Yang
Meixiang
M
Shao
Qianqian
Q
Wang
Donghai
D
Liu
Shuxun
S
Song
Haibo
H
Song
Bingfeng
B
Zhang
Yan
Y
Qu
Xun
X
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000262:Adenylyl Cyclases / Q000378:metabolism; D015687:Cell Hypoxia; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology*; D005786:Gene Expression Regulation; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D061965:Matrix Metalloproteinase Inhibitors; D009000:Monocytes / Q000166:cytology* / Q000201:enzymology; D043683:Receptors, Adenosine A2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D061965:Matrix Metalloproteinase Inhibitors; D043683:Receptors, Adenosine A2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020780:Matrix Metalloproteinase 9; D000262:Adenylyl Cyclases