Previously we have purified a cathepsin L-specific inhibitor from psoriatic epidermis and named as psoriastatin. Cloning of this inhibitor demonstrated that two similar but distinct types of cDNAs were expressed in psoriatic epidermis (90.8% identical each other). Psoriastatin type-I was 98% identical to SCCA and psoriastatin type-II was found to be SCCA2 itself which was recently reported from genomic cloning. Both types of psoriastatin/SCCA belong to serine proteinase inhibitor family, serpin. Among serpins, they showed the highest homology to ovserpin subfamily which includes Crm A, a suppressor of apoptosis. We therefore investigated the effect of psoriastatins on apoptotic cell death. Psoriastatin cDNAs were subcloned into the mammalian expression vector, pcDNA3 and transfected into human dermal fibroblasts. Psoriastatin-bearing cells were selected under G418 over three passages. Expression of both types were confirmed with immunocytochemistry using antipsoriastatin antibody. Apoptosis was induced in these cells by TNF-α and cyclohexamide stimulation. Both type-I and type-II transfected cells showed considerable resistance to these apoptotic stimuli and most of the cells were survived in contrast to the control fibroblasts which were transfected with vector only. TUNEL method also demonstrated that positive staining was markedly decreased in psoriastatin transfected cells. Our results indicated that psoriastatins function as suppressor of apoptosis. Abnormal proliferation and altered differentiation of keratinocytes could be due to the suppression of apoptosis by the overexpression of psoriastatin type-I and type-II which were not found in normal epidermis.