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 ho rmone receptors for glucocorticoids, retinoids, and vitamin D. The peroxiso me proliferator-activated receptor-gamma (PPAR gamma) is a related nuclear hormone receptor that can be activated by its ligands, including the thiazo lidinediones. Objective: To assess whether treatment with troglitazone, a currently avail able thiazolidinedione used to treat diabetes mellitus, has an effect on ps oriasis in normoglycemic patients and whether ligands for PPAR gamma have a n effect on models of psoriasis. Design: Open-label administration of troglitazone in patients with psoriasi s and evaluation of drug actions in cellular, organ, and transplant models of psoriasis. Setting: University and community hospital outpatient departments and unive rsity laboratories. Patients: Patients with chronic, stable plaque psoriasis and control subjec ts. Five patients with psoriasis received troglitazone (none withdrew); 10 different untreated patients and 10 controls provided tissue samples. Interventions: Oral troglitazone therapy at various dosages in patients wit h psoriasis; also, use of troglitazone, ciglitazone, and 15-deoxy-Delta-12, 14-prostaglandin J(2) in psoriasis models. Main Outcome Measures: 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 PPAR gamma inhibited the proliferation of normal and psoriatic human keratinocytes in culture. Troglitazone treatmen t normalized the histological features of psoriatic skin in organ culture a nd reduced the epidermal hyperplasia of psoriasis in the severe combined im munodeficient mouse and human skin transplant model of psoriasis (P<.05 com pared with untreated controls). Conclusions: Peroxisome proliferator-activated receptor-gamma might be a us eful intracellular target for the treatment of psoriasis; further study is needed to assess the clinical value of ligands for PPAR gamma, including tr oglitazone.