Inhibition of the transforming growth factor beta (TGFbeta) pathway by interleukin-1beta is mediated through TGFbeta-activated kinase 1 phosphorylation of SMAD3.
Transforming growth factor beta is the prototype of a large family of secreted factors that regulate multiple biological processes. In the immune system, TGFbeta acts as an anti-inflammatory and immunosuppressive molecule, whereas the cytokine interleukin (IL)-1beta is a crucial mediator of inflammatory responses and induces proinflammatory genes and acute phase proteins. Here, we present evidence for the existence of a direct inhibitory interaction between the IL-1beta and TGFbeta signaling cascades that is not dependent on IL-1beta-induced SMAD7 expression. IL-1beta and its downstream mediator TAK1 inhibit SMAD3-mediated TGFbeta target gene activation, whereas SMAD3 nuclear translocation and DNA binding in response to TGFbeta are not affected. IL-1beta transiently induces association between TAK1 and the MAD homology 2 domain of SMAD3, resulting in SMAD3 phosphorylation. Furthermore, IL-1beta alleviates the inhibitory effect of TGFbeta on in vitro hematopoietic myeloid colony formation. In conclusion, our data provide evidence for the existence of a direct inhibitory effect of the IL-1beta-TAK1 pathway on SMAD3-mediated TGFbeta signaling, resulting in reduced TGFbeta target gene activation and restored proliferation of hematopoietic progenitors.
Benus
Germaine F J D
GF
Developmental Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9751 NN Haren, The Netherlands.
Wierenga
Albertus T J
AT
de Gorter
David J J
DJ
Schuringa
Jan Jacob
JJ
van Bennekum
Ariëtte M
AM
Drenth-Diephuis
Loes
L
Vellenga
Edo
E
Eggen
Bart J L
BJ
D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D004247:DNA; D007375:Interleukin-1; D020930:MAP Kinase Kinase Kinases; D016212:Transforming Growth Factor beta; D000099151:MAP Kinase Kinase Kinase 7