Dose-dependent cross-talk between the transforming growth factor-β and interleukin-1 signaling pathways

Some tumor cell lines secrete high concentrations of TGFβ or IL-1. Similarly high concentrations of each of these cytokines cross-activate the other pathway: TGFβ activates NFκB, and IL-1β activates Smads. The IL-1 signaling components IRAK, MyD88, TRAF6, and TAK1 are all required for cross-activation of NFκB by TGFβ. Knockdown experiments revealed that both TGFβ receptor subunits are required for IL-1β to activate Smads, and the IL-1 receptor is required for TGFβ to activate NFκB. Coimmunoprecipitations showed that either TGFβ or IL-1β stimulate ligand-dependent association of all three receptor subunits. Furthermore, cross-talk between the TGFβ and IL-1 signaling pathways leads to dose-dependent cross-control of gene expression. These interactions provide new insight into biological responses to IL-1 and TGFβ in the proximity of tumors that secrete high concentrations of these factors and probably also at sites of inflammation, where the local concentrations of these cytokines are likely to be high.