It is now recognized that ultraviolet (UV) radiation is a potent environmental insult capable of interfering with immunity to skin cancers and modifying certain immunologic reactions within both locally irradiated skin and distant, unexposed sites. Exposure to UVB light (290-320 nm) induces a potent cutaneous inflammatory response that involves the infiltration of leukocytes into the dermis as well as the production of proinflammatory cytokines by both resident epidermal keratinocytes and dermal cells. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that has been shown to be a major mediator of UVB light effects on cutaneous immunity. Recent studies have demonstrated that pentoxifylline (PTX), a xanthine-derived phosphodiesterase inhibitor, has the ability to inhibit synthesis of TNF-alpha. To examine the effects of PTX on UVB-mediated cutaneous inflammation, Skh/hr hairless mice were injected intraperitoneally with either phosphate-buffered saline or 50 microg/g PTX 1 h before exposure to 2240 J/m2 UVB. Reverse transcription-polymerase chain reaction and immunohistochemical techniques were used to demonstrate that 24 h to 1 wk after UVB-light irradiation, PTX inhibited UVB-induced TNF-alpha gene expression, inhibited the increase in epidermal TNF-alpha protein synthesis, blocked the increase in epidermal proliferation observed after exposure to UVB light, and decreased production of myeloperoxidase by neutrophils infiltrating into the dermis. These studies demonstrated that PTX modifies epidermal responses after acute UVB light exposure and suggest that PTX treatment may be used clinically to modulate the deleterious effects of long-term UVB-light irradiation.