Human monocytes respond to extracellular cAMP through A2A and A2B adenosine receptors

Abstract

In this study, we test the hypothesis that cAMP, acting as an extracellular mediator, affects the physiology and function of human myeloid cells. The cAMP is a second messenger recognized as a universal regulator of several cellular functions in different organisms. Many studies have shown that extracellular cAMP exerts regulatory functions, acting as first mediator in multiple tissues. However, the impact of extracellular cAMP on cells of the immune system has not been fully investigated. We found that human monocytes exposed to extracellular cAMP exhibit higher expression of CD14 and lower amount of MHC class I and class II molecules. When cAMP-treated monocytes are exposed to proinflammatory stimuli, they exhibit an increased production of IL-6 and IL-10 and a lower amount of TNF-␣ and IL-12 compared with control cells, resembling the features of the alternative-activated macrophages or M2 macrophages. In addition, we show that extracellular cAMP affects monocyte differentiation into DCs, promoting the induction of cells displaying an activated, macrophage-like phenotype with reduced capacity of polarized, naive CD4 ϩ T cells into IFN-␥-producing lymphocytes compared with control cells. The effects of extracellular cAMP on monocytes are mediated by CD73 ecto-5=-nucleotidase and A2A and A2B adenosine receptors, as selective antagonists could reverse its effects. Of note, the expression of CD73 molecules has been found on the membrane of a small population of CD14 ϩ CD16 ϩ monocytes. These findings suggest that an extracellular cAMP-adenosine pathway is active in cells of the immune systems. J. Leukoc. Biol. 96: 113-122; 2014.

Prostaglandin E2-mediated adenosinergic effects on CD14+cells: Self-amplifying immunosuppression in cancer

“…Human monocytes and macrophages are largely CD73 negative but express CD39. 13 Although CD73 upregulation has been reported on other cell types, such as on T cells, epithelial cells, 30 endothelial cells 18 and murine leukocytes, 17 such an observation has only recently been made on human macrophages in ovarian cancer. 31 We have reported earlier that tumor cells may be present in mesothelioma PE 24 and here we demonstrate that these tumor cells in PE may express CD73 but not CD39.…”

“…11 Mouse peritoneal macrophages may also co-express these enzymes, 12 whereas healthy non-activated human blood monocytes and macrophages have abundant expression of CD39 but not CD73 on the cell surface. 13,14 Ectonucleotidase expression can be controlled by the microenvironment; e.g., CD39 expression is regulated by IL-27 in ovarian cancer, 15 while CD73 is upregulated by hypoxia on epithelial cells 16 by TGFb on murine leukocytes 17 and by signal-transducer and activator of transcription-3 (STAT3) activation on murine Th17 cells. 10 Endothelial cells were observed to respond to increased intracellular cAMP levels via an adenosine-mediated paracrine pathway leading to CD73 upregulation.…”

The yin and yang functions of extracellular ATP and adenosine in tumor immunity

“…For mature DCs, ADO increases cAMP and IL-10 secretion while inhibits IL-12 and TNF-α production [77]. ADO is also found to activate human monocyte-derived DCs through A2AR [78] and murine bone marrow-derived dendritic cells (BMDCs) through A2BR [79]. However, unlike normal myeloid DCs, ADO-differentiated DCs have impaired allostimulatory activity and express high levels of angiogenic, pro-inflammatory, immune suppressor and tolerogenic factors [80].…”

Polarization of immune responses in fish: The ‘macrophages first’ point of view

“…Human macrophages can also directly sense extracellular cAMP, inducing a phenotype resembling M2 macrophages. It is likely that a direct influx of cAMP into the cell or activation of adenylyl cyclases via adenosine receptors leads to an increase of intracellular second messenger cAMP, controlling the anti-inflammatory effects on monocytes (Sciaraffia et al, 2014). Macrophages of common carp stimulated with exogenous cAMP increase arginase activity but not NO production, and the induced arginase activity could be specifically inhibited by the NOS inhibitor N(omega)-hydroxy-nor-L-arginine (NOHA) (Joerink et al, 2006c).…”