Modulation of epidermal differentiation, tissue inflammation, and T-lymphocyte infilitration in psoriatic plaques by topical calcitriol.
Psoriasis is characterized by immune activation, increased proliferation and abnormal differentiation of keratinocytes. The reported anti-psoriatic mechanisms of action in vivo of vitamin D analogues include reduction of keratinocyte proliferation and induction of keratinocyte terminal differentiation. We investigated whether the anti-psoriatic effect of the natural active vatamin D analogue, calcitriol, applied topically, is due to direct effects on keratinocytes alone or also due to immunoregulatory effects of calcitriol. Psoriasis patients were treated with topical calcitriol (0.005%) and a vehicle control for 8 weeks. Disease activity was assessed by a severity index and quantitative histopathological markers. In vitro studies of lymphocyte proliferation and gamma interferon secretion and of keratinocyte proliferation complemented the clinicohistopathologic studies. A heterogeneous response to calcitriol treatment could be segregated based upon elimination of K-16 keratin expression. Calcitriol treatment decreased keratinocyte proliferation, normalized keratinocyte differentiation and decreased immune activation in plaques. The histologic response to vitamin D treatment of psoriasis includes suppression of both immune and keratinocyte activation in situ. These studies provide a basis for rational combination of anti-psoriatic treatments and for the design of new vitamin D analogues to treat psoriasis.
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY, USA.
I
I
Lu
P
P
Gilleaudeau
J A
JA
McLane
N
N
Heftler
M
M
Kamber
S
S
Gottlieb
J G
JG
Krueger
A B
AB
Gottlieb
D000287:Administration, Topical; D002117:Calcitriol / Q000008:administration & dosage / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004848:Epithelium / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D007633:Keratins / Q000096:biosynthesis; D011565:Psoriasis / Q000188:drug therapy*; D013601:T-Lymphocytes / Q000187:drug effects*
D007633:Keratins; D002117:Calcitriol