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

Some tumor cell lines secrete high concentrations of TGF beta or IL-1. Similarly high concentrations of each of these cytokines cross-activate the other pathway: TGF beta activates NN kappa B, and IL-1 beta activates Smads. The IL-1 signaling components IRAK, MyD88, TRAF6, and TAK1 are all required for cross-activation of NF kappa B by TGF beta. Knockdown experiments revealed that both TGF beta receptor subunits are required for IL-1 beta to activate Smads, and the IL-1 receptor is required for TGF beta to activate NF kappa B. Coimmunoprecipitations showed that either TGF beta or IL-1 beta stimulate ligand-dependent association of all three receptor subunits. Furthermore, cross-talk between the TGF beta 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 TGF beta 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.