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Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors

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Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors

dc.contributor.author	Perez-Aso, Miguel
dc.contributor.author	Montesinos Mezquita, María Carmen
dc.contributor.author	Mediero, Aránzazu
dc.contributor.author	Wilder, Tuere
dc.contributor.author	Schafer, Peter H.
dc.contributor.author	Cronstein, Bruce
dc.date.accessioned	2017-06-01T17:16:58Z
dc.date.available	2017-06-01T17:16:58Z
dc.date.issued	2015
dc.identifier.uri	http://hdl.handle.net/10550/58806
dc.description.abstract	Introduction This work was undertaken to delineate intracellular signaling pathways for the PDE4 inhibitor apremilast and to examine interactions between apremilast, methotrexate and adenosine A2A receptors (A2AR). Methods After apremilast and LPS incubation, intracellular cAMP, TNF-α, IL-10, IL-6 and IL-1α were measured in the Raw264.7 monocytic murine cell line. PKA, Epac1/2 (signaling intermediates for cAMP) and A2AR knockdowns were performed by shRNA transfection and interactions with A2AR and A2BR, as well as with methotrexate were tested in vitro and in the murine air pouch model. Statistical differences were determined using one or two-way ANOVA or Student's t test. The alpha nominal level was set at 0.05 in all cases. A P value of < 0.05 was considered significant. Results In vitro, apremilast increased intracellular cAMP and inhibited TNF-α release (IC50=104nM) and the specific A2AR-agonist CGS21680 (1μM) increased apremilast potency (IC50=25nM). In this cell line, apremilast increased IL-10 production. PKA, Epac1 and Epac2 knockdowns prevented TNF-α inhibition and IL-10 stimulation by apremilast. In the murine air pouch model, both apremilast and MTX significantly inhibited leukocyte infiltration, while apremilast, but not MTX, significantly inhibited TNF-α release. The addition of MTX (1 mg/kg) to apremilast (5 mg/kg) yielded no more inhibition of leukocyte infiltration or TNF-α release than with apremilast alone. Conclusions The immunoregulatory effects of apremilast appear to be mediated by cAMP through the downstream effectors PKA, Epac1, and Epac2. A2AR agonism potentiated TNF-α inhibition by apremilast, consistent with the cAMP-elevating effects of that receptor. Because the A2AR is also involved in the anti-inflammatory effects of MTX, the mechanism of action of both drugs involves cAMP-dependent pathways and is therefore partially overlapping in nature.
dc.language.iso	eng
dc.relation.ispartof	Arthritis Research & Therapy, 2015, vol. 17, p. 249
dc.rights.uri	info:eu-repo/semantics/openAccess
dc.source	Perez-Aso, Miguel Montesinos Mezquita, Mª Carmen Mediero, Aránzazu Wilder, Tuere Schafer, Peter H. Cronstein, Bruce 2015 Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors Arthritis Research & Therapy 17 249
dc.subject	Artritis
dc.subject	Medicaments
dc.title	Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors
dc.type	info:eu-repo/semantics/article
dc.date.updated	2017-06-01T17:16:59Z
dc.identifier.doi	https://doi.org/10.1186/s13075-015-0771-6
dc.identifier.idgrec	108771