The cAMP Pathway as Therapeutic Target in Autoimmune and Inflammatory Diseases

Verena Katharina Raker, Christian Becker, Kerstin Steinbrink, Verena Katharina Raker, Christian Becker, Kerstin Steinbrink

Abstract

Nucleotide signaling molecules contribute to the regulation of cellular pathways. In the immune system, cyclic adenosine monophosphate (cAMP) is well established as a potent regulator of innate and adaptive immune cell functions. Therapeutic strategies to interrupt or enhance cAMP generation or effects have immunoregulatory potential in autoimmune and inflammatory disorders. Here, we provide an overview of the cyclic AMP axis and its role as a regulator of immune functions and discuss the clinical and translational relevance of interventions with these processes.

Keywords: T cells; T regulatory cells; Tregs; autoimmunity; cyclic AMP; inflammation; targeted therapies.

Figures

Figure 1
Figure 1
cAMP as a regulator of immunity. Adenylate cyclases (AC) produce cAMP from adenosin-tri-phosphate (ATP). High levels of cytosolic cAMP lead to activation of protein kinase A (PKA). PKA stimulation induces the phosphorylation of transcription factors, such as CREB, ICER/CREM, ATF-1, and CBP to drive camp-driven genes. Phosphodiesterase 4 (PDE4) decreases intracellular cAMP levels and counterbalances the intracellular cAMP effect. ATF, cAMP-dependent transcription factor; CBP, cAMP-binding protein; CNG, cyclic nucleotide-gated ion channel; CREB, cAMP response element-binding protein; ICER, inducible cAMP early repressor; P, phosphorylation.
Figure 2
Figure 2
Effect of cAMP on immune, tumor, and epithelial cells. Impact and function of cyclic adenosin monophopshate (cAMP) on T and B lymphocytes, granulocytes, monocytes, macrophages, dendritic cells, epithelial cells, and melanoma cells. LTB4, leukotriene B4; LTC4, leukotriene C4.
Figure 3
Figure 3
The cAMP pathway in Treg and its regulation by IFN-α. Signaling via the T cell receptor (TCR) leads to an activation of adenylate cyclases, resulting in high cAMP levels in regulatory T cells (Treg). cAMP can be transferred via gap junctions into conventional T cells (Tcon), thereby mediating the suppressive activity of Treg (A). Phosphodiesterase 4 (PDE4), which can be activated by MAP kinase ERK-related pathways, reduces cAMP amounts in Treg by enzymatic cleavage, impairing the regulatory activity of Treg (B). IFN-α abolishes the suppressive function of Treg by cAMP reduction, restoring the Tcon activation. Inhibition of the ERK or PDE4 pathway, respectively, results in a renewed suppressive capacity of IFN-α treated Treg (C).
Figure 4
Figure 4
Function of cAMP in the interaction of conventional and regulatory T cells. In contrast to Tcon (blue line), Treg (green line) exhibit high levels of cAMP (A). Stimulated Tcon display a high proliferation whereas Treg are characterized by a low proliferative capacity [(B), left panels, single culture]. Treg efficiently inhibit Tcon proliferation in co-culture experiments by cAMP transfer via gap junctions to Tcon [(B), co-culture]. By contrast, IFN-α abrogates the suppressive function of Treg through reduction of cAMP levels [(A), centered panel], resulting in a restored Tcon activation [(B), centered panel]. Blockade of the ERK or PDE4 pathway, respectively, increases intracellular cAMP amounts [(A), right panel], renews the suppressive activity of Treg [(B), right panel]. Tcon, conventional T cells; Treg, regulatory T cells.

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