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Vol. 16, Issue 8, 3501-3510, August 2005

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Inhibition of the Transforming Growth Factor (TGF) Pathway by Interleukin-1 Is Mediated through TGF-activated Kinase 1 Phosphorylation of SMAD3

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

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

Submitted November 30, 2004; Revised May 9, 2005; Accepted May 17, 2005
Monitoring Editor: William Tansey

Transforming growth factor is the prototype of a large family of secreted factors that regulate multiple biological processes. In the immune system, TGF acts as an anti-inflammatory and immunosuppressive molecule, whereas the cytokine interleukin (IL)-1 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 and TGF signaling cascades that is not dependent on IL-1–induced SMAD7 expression. IL-1 and its downstream mediator TAK1 inhibit SMAD3-mediated TGF target gene activation, whereas SMAD3 nuclear translocation and DNA binding in response to TGF are not affected. IL-1 transiently induces association between TAK1 and the MAD homology 2 domain of SMAD3, resulting in SMAD3 phosphorylation. Furthermore, IL-1 alleviates the inhibitory effect of TGF 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-TAK1 pathway on SMAD3-mediated TGF signaling, resulting in reduced TGF target gene activation and restored proliferation of hematopoietic progenitors.

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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