Chimeric extracellular domain of type II transforming growth factor (TGF)-β receptor fused to the Fc region of human immunoglobulin as a TGF-β antagonist

Transforming growth factor-beta (TGF-beta) type-I and type-II receptors form a ligand-dependent heteromeric signalling complexes, in which transforming growth factor-beta receptor type II (T beta RII) trends to act as the primary receptor. In the present study, we used a chimeric soluble type-II receptor fused with the Fc regions of human immunoglobulin (T beta RIIs-Fc) in order to obtain a putative TGF-beta antagonist. Biochemical studies revealed that T beta RIIs-Fc shared the same properties as the wild-type receptor. The T beta RIIs-Fc receptor displayed an affinity of 1370 +/- 363 pM which was similar to those of the wild-type T beta RII when expressed alone in Cos-1 cells (1122 +/- 413 pM). Furthermore, the chimeric receptor showed the same selectivity for TGF-beta isoforms as the native receptor. Although both TGF-beta 1 and TGF-beta 3 were able to bind TI beta RIIs-Fc, TGF-beta 2 could not compete with the binding of TGF-beta 1 to T beta RIIs-Fc. It was noted that this type of fused Fc receptor could be used in FlashPlate screening for potent agonism and antagonism of TGF beta. Moreover, biological activities of the chimeric receptor showed it to be a potent TGF-beta 1-antiproliferative and TGF-beta 1-extracellular matrix transcriptional inhibitor on responses in Mv1Lu cells. To conclude, our results clearly show that the T beta RIIs-Fc chimeric receptor could be used as a potent TGF-beta antagonist. These data raised the possibility that this T beta RIIs-Fc construct might act successfully as an antagonist of both TGF-beta 1 and TGF-beta 3 in vitro.