Elsevier

Cellular Signalling

Volume 26, Issue 9, September 2014, Pages 2016-2029
Cellular Signalling

Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity

https://doi.org/10.1016/j.cellsig.2014.05.014Get rights and content
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Highlights

  • The current analyses studied the pharmacodynamic properties of apremilast.

  • Apremilast activates the CREB/ATF-1 pathway and does not bind to human cereblon.

  • Apremilast does not affect B/T-cell expansion or immunoglobulin production.

  • Effects of apremilast on innate immunity are greater than on adaptive immunity.

  • Apremilast is a selective inhibitor of PDE4 that regulates inflammatory mediators.

Abstract

Apremilast, an oral small molecule inhibitor of phosphodiesterase 4 (PDE4), is in development for chronic inflammatory disorders, and has shown efficacy in psoriasis, psoriatic arthropathies, and Behçet's syndrome. In March 2014, the US Food and Drug Administration approved apremilast for the treatment of adult patients with active psoriatic arthritis. The properties of apremilast were evaluated to determine its specificity, effects on intracellular signaling, gene and protein expression, and in vivo pharmacology using models of innate and adaptive immunity. Apremilast inhibited PDE4 isoforms from all four sub-families (A1A, B1, B2, C1, and D2), with IC50 values in the range of 10 to 100 nM. Apremilast did not significantly inhibit other PDEs, kinases, enzymes, or receptors. While both apremilast and thalidomide share a phthalimide ring structure, apremilast lacks the glutarimide ring and thus fails to bind to cereblon, the target of thalidomide action. In monocytes and T cells, apremilast elevated intracellular cAMP and induced phosphorylation of the protein kinase A substrates CREB and activating transcription factor-1 while inhibiting NF-κB transcriptional activity, resulting in both up- and down-regulation of several genes induced via TLR4. Apremilast reduced interferon-α production by plasmacytoid dendritic cells and inhibited T-cell cytokine production, but had little effect on B-cell immunoglobulin secretion. In a transgenic T-cell and B-cell transfer murine model, apremilast (5 mg/kg/day p.o.) did not affect clonal expansion of either T or B cells and had little or no effect on their expression of activation markers. The effect of apremilast on innate immunity was tested in the ferret lung neutrophilia model, which allows monitoring of the known PDE4 inhibitor gastrointestinal side effects (nausea and vomiting). Apremilast significantly inhibited lung neutrophilia at 1 mg/kg, but did not induce significant emetic reflexes at doses < 30 mg/kg. Overall, the pharmacological effects of apremilast are consistent with those of a targeted PDE4 inhibitor, with selective effects on innate immune responses and a wide therapeutic index compared to its gastrointestinal side effects.

Abbreviations

ANOVA
analysis of variance
ATF-1
activating transcription factor-1
CCL-2
chemokine ligand 2
CCL-8
chemokine ligand 8
CCL-18
chemokine ligand 18
CCR-1
chemokine receptor 1
CRBN
cereblon
CRE
cAMP responsive element
CREB
cAMP responsive element binding protein
CXCL-5
CXC cytokine ligand 5
DCs
dendritic cells
DMSO
dimethyl sulfoxide
EC50
half-maximal effective concentration
ED50
half-maximal effective drug concentration
ELISA
enzyme-linked immunosorbent assay
Epac
exchange proteins activated by cAMP
FP
fluorescence polarization
HEL
hen egg lysozyme
IC50
half-maximal inhibitory concentration
Ig
immunoglobulin
IL
interleukin
IP-10
interferon-inducible protein 1
LPS
lipopolysaccharide
MCP-1
monocyte chemoattractant protein 1
MCP-2
monocyte chemoattractant protein 2
MHC
major histocompatibility complex
MIP-1αR
macrophage inflammatory protein 1-α receptor
MIP-4
macrophage inflammatory protein-4
MX1
myxovirus resistant 1
NF-κB
nuclear factor-kappa B
NK
natural killer
OVA
ovalbumin
PBMCs
peripheral blood mononuclear cells
PBS
phosphate-buffered saline
PDE4
phosphodiesterase 4
PKA
protein kinase A
PsA
psoriatic arthritis
SOCS-3
suppressor of cytokine signaling 3
TLR
toll-like receptor
TNF
tumor necrosis factor

Keywords

Apremilast
Phosphodiesterase inhibitor
Preclinical drug evaluation
Psoriasis
Psoriatic arthritis
Spondyloarthropathies

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