Troglitazone improves psoriasis and normalizes models of proliferative skin disease: ligands for peroxisome proliferator-activated receptor-gamma inhibit keratinocyte proliferation.
BACKGROUND
Psoriasis is often treated with agents that activate nuclear hormone receptors for glucocorticoids, retinoids, and vitamin D. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a related nuclear hormone receptor that can be activated by its ligands, including the thiazolidinediones.


OBJECTIVE
To assess whether treatment with troglitazone, a currently available thiazolidinedione used to treat diabetes mellitus, has an effect on psoriasis in normoglycemic patients and whether ligands for PPARgamma have an effect on models of psoriasis.


METHODS
Open-label administration of troglitazone in patients with psoriasis and evaluation of drug actions in cellular, organ, and transplant models of psoriasis.


METHODS
University and community hospital outpatient departments and university laboratories.


METHODS
Patients with chronic, stable plaque psoriasis and control subjects. Five patients with psoriasis received troglitazone (none withdrew); 10 different untreated patients and 10 controls provided tissue samples.


METHODS
Oral troglitazone therapy at various dosages in patients with psoriasis; also, use of troglitazone, ciglitazone, and 15-deoxy-delta-12,14-prostaglandinJ2 in psoriasis models.


METHODS
Investigator-determined clinical results in patients and cell counts and histological evidence in models.


RESULTS
All patients' psoriasis improved substantially during troglitazone therapy. Peroxisome proliferator-activated receptor-gamma was expressed in human keratinocytes; ligands for PPARgamma inhibited the proliferation of normal and psoriatic human keratinocytes in culture. Troglitazone treatment normalized the histological features of psoriatic skin in organ culture and reduced the epidermal hyperplasia of psoriasis in the severe combined immunodeficient mouse and human skin transplant model of psoriasis (P<.05 compared with untreated controls).


CONCLUSIONS
Peroxisome proliferator-activated receptor-gamma might be a useful intracellular target for the treatment of psoriasis; further study is needed to assess the clinical value of ligands for PPARgamma, including troglitazone.
Ellis
C N
CN
Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109-0314, USA.
Varani
J
J
Fisher
G J
GJ
Zeigler
M E
ME
Pershadsingh
H A
HA
Benson
S C
SC
Chi
Y
Y
Kurtz
T W
TW
D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D002454:Cell Differentiation; D002839:Chromans / Q000378:metabolism / Q000627:therapeutic use*; D017931:DNA Primers; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D008024:Ligands; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012871:Skin Diseases / Q000188:drug therapy* / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism / Q000627:therapeutic use*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000077288:Troglitazone
D000970:Antineoplastic Agents; D002839:Chromans; D017931:DNA Primers; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077288:Troglitazone