Inhibition of the Transforming Growth Factor β (TGFβ) Pathway by Interleukin-1β Is Mediated through TGFβ-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.