The effects of prostaglandin E1 (PGE1) on cell growth, cytokine production and interaction of cultured normal human keratinocytes (NHKs) and human dermal fibroblasts (HDFs) were investigated. When NHKs were treated with PGE1 directly, only a slight increase in cell growth and a transient decrease in interleukin 1 alpha (IL-1 alpha) secretion were observed. No IL-6 was detected either before or after PGE1 treatment. In addition, IL-8 and transforming growth factor alpha (TGF alpha) production were uninfluenced by PGE1. The response of HDFs to PGE1 differed from that of NHKs. Following PGE1 treatment, IL-1 alpha and TGF alpha from HDFs remained undetectable while IL-6 production was enhanced markedly. IL-8 production was also slightly enhanced. Exposure of HDFs to PGE1 for 96 hours significantly promoted cell proliferation. Two kinds of conditioned media (CM) were prepared by a brief feeding of HDFs with keratinocyte basic medium or Dulbecco's modified Eagle's medium supplemented with 5% FCS with or without PGE1. NHKs proliferated more rapidly in CM than in corresponding basic medium. Moreover, CM prepared with PGE1 treatment showed a stronger effect in promoting NHK proliferation than CM without PGE1 treatment. This promoting effect was inhibited by anti-human IL-6 monoclonal antibody dose-dependently. These results indicate that fibroblasts are more sensitive than keratinocytes in response to PGE1 and that, upon PGE1 stimulation, HDF-derived IL-6 may play an essential role in NHK cell proliferation which may at least partly account for the beneficial effects of PGE1 in the treatment of cutaneous ulcerations.