IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.
Aberrant cytokine expression has been proposed as an underlying cause of psoriasis, although it is unclear which cytokines play critical roles. Interleukin (IL)-23 is expressed in human psoriasis and may be a master regulator cytokine. Direct intradermal administration of IL-23 in mouse skin, but not IL-12, initiates a tumor necrosis factor-dependent, but IL-17A-independent, cascade of events resulting in erythema, mixed dermal infiltrate, and epidermal hyperplasia associated with parakeratosis. IL-23 induced IL-19 and IL-24 expression in mouse skin, and both genes were also elevated in human psoriasis. IL-23-dependent epidermal hyperplasia was observed in IL-19-/- and IL-24-/- mice, but was inhibited in IL-20R2-/- mice. These data implicate IL-23 in the pathogenesis of psoriasis and support IL-20R2 as a novel therapeutic target.
Chan
Jason R
JR
Discovery Research, Schering-Plough Biopharma (formerly DNAX Research, Inc.), Palo Alto, CA 94304, USA.
Blumenschein
Wendy
W
Murphy
Erin
E
Diveu
Caroline
C
Wiekowski
Maria
M
Abbondanzo
Susan
S
Lucian
Linda
L
Geissler
Richard
R
Brodie
Scott
S
Kimball
Alexa B
AB
Gorman
Daniel M
DM
Smith
Kathleen
K
de Waal Malefyt
Rene
R
Kastelein
Robert A
RA
McClanahan
Terrill K
TK
Bowman
Edward P
EP
D000818:Animals; D004817:Epidermis / Q000254:growth & development / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D006965:Hyperplasia; D053759:Interleukin-23 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011565:Psoriasis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D053759:Interleukin-23; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D014409:Tumor Necrosis Factor-alpha; C492510:interleukin-20 receptor