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

Abstract

Some tumor cell lines secrete high concentrations of TGF␤ or IL-1. Similarly high concentrations of each of these cytokines cross-activate the other pathway: TGF␤ activates NFB, and IL-1␤ activates Smads. The IL-1 signaling components IRAK, MyD88, TRAF6, and TAK1 are all required for cross-activation of NFB by TGF␤. Knockdown experiments revealed that both TGF␤ receptor subunits are required for IL-1␤ to activate Smads, and the IL-1 receptor is required for TGF␤ to activate NFB. Coimmunoprecipitations showed that either TGF␤ or IL-1␤ stimulate ligand-dependent association of all three receptor subunits. Furthermore, cross-talk between the TGF␤ 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␤ 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.cytokine receptors ͉ NFB ͉ Smad ͉ TLRs M embers of the TGF␤ superfamily regulate many developmental processes, and TGF␤ is involved in many human diseases, including cancer, where it functions, paradoxically, both as an antiproliferative factor and a tumor promoter (1). The TGF␤ receptor (T␤R) is a complex of two single-pass transmembrane subunits, T␤RI and T␤RII, which contain intracellular serine/ threonine kinase domains. Ligand binding induces T␤RI and T␤RII to associate, leading to the phosphorylation of T␤RI by T␤RII, activating its kinase domain. Activated T␤RI then phosphorylates and activates the transcription factors Smad 2 and Smad 3 (1, 2). TGF␤ can also activate other signaling proteins, including MAP kinases and, especially relevant to the work reported here, NFB (3, 4). The balance between Smad activation and other signals is likely to help determine whether TGF␤ suppresses or promotes cancer (1, 2).IL-1 plays a crucial role in inflammation, stress, and disease (5, 6). IL-1␣ or IL-1␤ bind to and activate the IL-1 receptor (IL-1R) (5). IL-1R and the adaptor protein myeloid differentiation factor 88 (MyD88) interact through their intracellular domains (5-7). The death domain of MyD88 then recruits the IL-1R-associated kinase (IRAK) to the receptor complex (5, 7). IRAK is phosphorylated, dissociates from the receptor complex, and recruits tumor necrosis factor ␣ receptor-associated factor 6 (TRAF6), which in turn activates the downstream kinase TGF␤ activating kinase 1 (TAK1), eventually leading to the activation of inhibitor of NFB (IB), the phosphorylation and degradation of IB, and the activation of NFB (5-8). Responses to IL-1 are amplified through an autocrine loop. For example, astrocytoma cells respond to treatment with IL-1␤ by up-regulating mRNAs encoding IL-1␣ or IL-1␤, IL-1R, and tumor necrosis factor ␣ mRNAs (9). Recent work reveals that this autocrine loop plays an important role in the development of resistance to the antitumor drug camptothecin, which induces the expression of IL-1␤ by activa...

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