Tumor necrosis factor alpha stimulates production of leukemia inhibitory factor in human dermal fibroblast cultures

Leukemia inhibitory factor (LIF) is a recently described cytokine with a variety of actions including a possible involvement in immune responses. We determined whether human dermal fibroblast cultures could produce LIF after they were treated with tumor necrosis factor alpha (TNF alpha), a cytokine that is produced as an early inflammatory response of activated monocytes. We found that treatment of the cultures with as little as 0.5 units/ml (1.5 pM) caused a detectable increase in both LIF message and protein as measured by Northern blot assay and ELISA, respectively. Furthermore, increasing concentrations of TNF alpha produced a dose-dependent increase in both steady-state LIF mRNA and protein levels up to a maximum response with 500 units/ml (1.5 nM). Increases in LIF mRNA levels were rapid and could be detected 1 hr after treatment with 500 units/ml of TNF alpha. However, this effect was transient. It reached a maximum at 2 hr and returned almost to baseline at 24 hr. In contrast, levels of LIF protein in the conditioned media of the cultures increased progressively over 24 hr. The LIF produced by these cultures was biologically active and was inhibited by a polyclonal antibody to human LIF in a bioassay. These results demonstrate that LIF is produced by human dermal fibroblasts in response to treatment with TNF alpha, a mediator of acute inflammation. Furthermore, they suggest that production of LIF by these cells may be involved in the development of both the local and generalized immune response.