Interleukin-1 alpha mediates the growth proliferative effects of transforming growth factor-beta in p21 null MCF-10A human mammary epithelial cells

Transforming growth factor-β type 1 (TGF-β) has been implicated as both a tumor suppressor and a tumor promoter in many solid epithelial cancers. We have previously demonstrated that the cyclin dependent kinase (CDK) inhibitor p21 acts as a molecular switch in determining a growth inhibitory versus growth proliferative response to TGF-β in the spontaneously immortalized human mammary epithelial cell line MCF-10A. We now demonstrate that this proliferative effect of TGF-β is mediated through the proinflammatory cytokine, interleukin-1α (IL-1α). Using gene expression array analysis, we identified IL-1α as a cytokine specifically upregulated only in cells lacking p21 and only upon TGF-β stimulation. Cell proliferation assays verified that recombinant IL-1α was capable of inducing a growth proliferative response in p21 null MCF-10A cells, while neutralizing antibodies against IL-1α prevented the growth proliferative effects of TGF-β. Mechanistically, both the CDK and proliferating cell nuclear antigen (PCNA) inhibitory functions of p21 were responsible for preventing TGF-β induced cell proliferation, but only PCNA inhibition by p21 regulated IL-1α gene expression. These studies demonstrate a novel role for IL-1α in mediating a proliferative response to TGF-β signaling, and suggest that therapies directed against IL-1α could abate the growth proliferative effects of TGF-β without compromising its tumor suppressive function.