Modulation of urokinase-type plasminogen activator gene expression by inflammatory cytokines in human pre-B lymphoma cell line RC-K8

We examined the effects of inflammatory cytokines, such as interleukin-1α (IL-1α), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNFα), transforming growth factor-β (TGFβ) and lipopolysaccharide (LPS), on the urokinase-type plasminogen activator (uPA) gene expression in RC-K8 human pre-B lymphoma cells. Recombinant IL-1α, recombinant IL-1β and LPS but not recombinant IL-6, recombinant TNFα and TGFβ dose-dependently increased uPA accumulation in the conditioned medium. Northern blot analysis revealed that uPA mRNA levels rapidly increased with a peak induction at 2 h after stimulation with IL-1α and IL-1β, but uPA mRNA increase by LPS began at 9 h after stimulation and the increase was maintained until the experiment ended at 24 h. These responses were independent of de novo synthesis, rather amplified in the presence of a protein synthesis inhibitor. The effects by IL-1α and IL-1β were prevented by addition of anti-IL-1α and anti-IL-1β neutralizing antibodies, respectively. In contrast, both antibodies did not prevent LPS-induced uPA gene expression. Therefore, it is unlikely that the effect by LPS is through induction of IL-1. Both IL-1α and IL-1β rapidly activated uPA gene transcription, but not increased stability of uPA mRNA. These results suggest that both IL-1α and IL-1β cause a rapid activation of uPA gene transcription in which de novo protein synthesis is not required and that LPS induces uPA gene expression independently of the IL-1 pathway. These modulations of uPA production by inflammatory mediators may be implicated in tumor growth and metastasis.