Dose-dependent cross-talk between the transforming growth factor-beta and interleukin-1 signaling pathways.
Some tumor cell lines secrete high concentrations of TGFbeta or IL-1. Similarly high concentrations of each of these cytokines cross-activate the other pathway: TGFbeta activates NFkappaB, and IL-1beta activates Smads. The IL-1 signaling components IRAK, MyD88, TRAF6, and TAK1 are all required for cross-activation of NFkappaB by TGFbeta. Knockdown experiments revealed that both TGFbeta receptor subunits are required for IL-1beta to activate Smads, and the IL-1 receptor is required for TGFbeta to activate NFkappaB. Coimmunoprecipitations showed that either TGFbeta or IL-1beta stimulate ligand-dependent association of all three receptor subunits. Furthermore, cross-talk between the TGFbeta 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 TGFbeta 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.
Lu
Tao
T
Department of Molecular Genetics, Lerner Research Institute, and Brain Tumor Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Tian
Liping
L
Han
Yulong
Y
Vogelbaum
Michael
M
Stark
George R
GR
D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D053583:Interleukin-1beta / Q000378:metabolism*; D008024:Ligands; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D053583:Interleukin-1beta; D008024:Ligands; D020930:MAP Kinase Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D016212:Transforming Growth Factor beta; D000099151:MAP Kinase Kinase Kinase 7; C507779:MYD88 protein, human