Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis.
OBJECTIVE
Apremilast is an orally administered phosphodiesterase-4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory effects of apremilast on pro-inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis.


METHODS
Apremilast was tested in vitro against endotoxin- and superantigen-stimulated PBMC, bacterial peptide and zymosan-stimulated polymorphonuclear cells, immunonoglobulin and cytokine-stimulated NK cells, and ultraviolet B light-activated keratinocytes. Apremilast was orally administered to beige-severe combined immunodeficient mice, xenotransplanted with normal human skin and triggered with human psoriatic NK cells. Epidermal skin thickness, proliferation index and inflammation markers were analysed.


RESULTS
Apremilast inhibited PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon-gamma and tumour necrosis factor (TNF)-alpha, and interleukins (IL)-2, IL-12 and IL-23. Production of TNF-alpha by NK cells and keratinocytes was also inhibited. In vivo, apremilast significantly reduced epidermal thickness and proliferation, decreased the general histopathological appearance of psoriasiform features and reduced expression of TNF-alpha, human leukocyte antigen-DR and intercellular adhesion molecule-1 in the lesioned skin.


CONCLUSIONS
Apremilast displayed a broad pattern of anti-inflammatory activity in a variety of cell types and decreased the incidence and severity of a psoriasiform response in vivo. Inhibition of TNF-alpha, IL-12 and IL-23 production, as well as NK and keratinocyte responses by this phosphodiesterase-4 inhibitor suggests a novel approach to the treatment of psoriasis.
Schafer
P H
PH
Department of Drug Discovery, Celgene Corporation, Summit, NJ 07901, USA. pschafer@celgene.com
Parton
A
A
Gandhi
A K
AK
Capone
L
L
Adams
M
M
Wu
L
L
Bartlett
J B
JB
Loveland
M A
MA
Gilhar
A
A
Cheung
Y-F
YF
Baillie
G S
GS
Houslay
M D
MD
Man
H-W
HW
Muller
G W
GW
Stirling
D I
DI
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004768:Enterotoxins / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011565:Psoriasis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D012867:Skin / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000528:radiation effects; D016038:Skin Transplantation; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014183:Transplantation, Heterologous; D020298:U937 Cells; D014466:Ultraviolet Rays; D015054:Zymosan / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004768:Enterotoxins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; C031818:enterotoxin B, staphylococcal; D013792:Thalidomide; D015054:Zymosan; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C505730:apremilast