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MBC in Press, published online ahead of print May 25, 2005
Mol. Biol. Cell 10.1091/mbc.E04-11-1033

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Submitted on November 30, 2004
Revised on May 9, 2005
Accepted on May 17, 2005

Inhibition of the TGF{beta} Pathway by IL-1{beta} Is Mediated through TAK1 Phosphorylation of SMAD3

Germaine F.J.D. Benus,*{dagger} Albertus T.J. Wierenga,{dagger}{ddagger} David J.J. de Gorter,* Jan Jacob Schuringa,* Ariëtte M. van Bennekum,* Loes Drenth-Diephuis,* Edo Vellenga,{ddagger} and Bart J.L. Eggen*

*Developmental Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9751 NN Haren, The Netherlands; {ddagger}Department of Hematology, University Hospital Groningen, 9713 GZ Groningen, The Netherlands

Monitoring Editor: William Tansey

Transforming growth factor {beta} is the prototype of a large family of secreted factors that regulate multiple biological processes. In the immune system, TGF{beta} acts as an antiinflammatory and immunosuppressive molecule whereas the cytokine interleukin 1 (IL-1{beta}) 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-1{beta} and TGF{beta} signaling cascades which is not dependent on IL-1{beta}-induced SMAD7 expression. IL-1{beta} and its downstream mediator TAK1 inhibit SMAD3-mediated TGF{beta} target gene activation whereas SMAD3 nuclear translocation and DNA binding in response to TGF{beta} are not affected. IL-1{beta} transiently induces association between TAK1 and the MH2 domain of SMAD3 resulting in SMAD3 phosphorylation. Furthermore, IL-1{beta} alleviates the inhibitory effect of TGF{beta} on in vitro hematopoietic myeloid colony formation. In conclusion, our data provide evidence for the existence of a direct inhibitory effect of the IL-1{beta}-TAK1 pathway on SMAD3-mediated TGF{beta} signaling, resulting in reduced TGF{beta}-target gene activation and restored proliferation of hematopoietic progenitors.

{dagger}These authors contributed equally to this work.

Address correspondence to: Bart J.L. Eggen (b.j.l.eggen{at}rug.nl)




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