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.