![]() In human monocyte-derived macrophages (MDM), the Epac1 expression level is highly increased, and in these cells cAMP-induced inhibition of FcR-mediated phagocytosis is mediated via both the PKA and the Epac1-Rap1 pathways. In monocytes, cAMP signals through PKA as well as via Epac1 to Rap1 however, cAMP inhibits immune functions only by activation of PKA and not via the Epac-Rap1 route. In this study, we investigated the effects of cAMP on human monocyte immune functions. cAMP analogues with specificity toward PKA (6-Bnz-cAMP) and Epac (8-CPT-2′-O-Me-cAMP) are useful tools to discriminate between PKA- and Epac-Rap-mediated signaling effects ( 36, 37). It is not known whether cAMP-mediated inhibition of immune responses is mediated through PKA activation or activation of the Epac1-Rap1 pathway. 26 and 27) and β integrins in a variety of cells, including intergrins of the β 2 family, and cAMP has recently been reported to control integrin-mediated cell adhesion via Epac-Rap1 ( 28, 29, 30, 31, 32, 33, 34, 35).Īlthough a number of studies of the effect of cAMP on immune functions have been performed, little has been reported on the effect of cAMP on isolated monocytes. Rap1 regulates cell adhesion (for a review, see Refs. Epac is a guanine exchange factor for the small GTPases Rap1 and Rap2 and has been shown to control a number of cellular processes previously attributed to PKA ( 25). However, exchange protein directly activated by cAMP (Epac) also functions as a receptor for cAMP ( 23, 24). PKA was earlier thought to be the primary effector of cAMP in eukaryotic cells. In lymphocytes, cAMP inhibits immune responses by a protein kinase A (PKA) 4 -dependent mechanism that involves activation of Csk localized to lipid rafts in the plasma membrane ( 22). Elevated levels of cAMP in immune cells generally lead to suppression of immune responses, including cytokine production, cell proliferation, chemotaxis, and phagocytosis ( 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). In conclusion, the Epac1-Rap1 pathway is present in both monocytes and macrophages, but only regulates specific immune effector functions in macrophages.Ĭyclic AMP regulates a wide range of cellular events, such as metabolism and gene expression, cell division, insulin secretion, exocytosis, and regulation of immune responses ( 1, 2, 3, 4, 5, 6). ![]() However, LPS-induced TNF-α production is only inhibited through the PKA pathway in these cells. Furthermore, we show that the level of Epac1 increases 3-fold during differentiation of monocytes into macrophages, and in monocyte-derived macrophages cAMP inhibits FcR-mediated phagocytosis via both PKA and the Epac1-Rap1 pathway. In contrast, activation of PKA by a PKA-specific compound (6-Bnz-cAMP) or physiological cAMP-elevating stimuli like PGE 2 inhibits monocyte immune functions. However, by using an Epac-specific cAMP analog (8-CPT-2′-O-Me-cAMP), we show that monocyte activation parameters such as synthesis and release of cytokines, stimulation of cell adhesion, chemotaxis, phagocytosis, and respiratory burst are not regulated by the Epac1-Rap1 pathway. ![]() In this study, we demonstrate the presence of Epac1 in human peripheral blood monocytes and activation of Rap1 in response to cAMP. Although elevation of cAMP in lymphocytes leads to suppression of immune functions by a PKA-dependent mechanism, the effector mechanisms for cAMP regulation of immune functions in monocytes and macrophages are not fully understood. CAMP mediates its intracellular effects through activation of protein kinase A (PKA), nucleotide-gated ion channels, or exchange protein directly activated by cAMP (Epac). ![]()
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