Chimeric extracellular domain type II transforming growth factor (TGF)-beta receptor fused to the Fc region of human immunoglobulin as a TGF-beta 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 (TbetaRII) 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 (TbetaRIIs-Fc) in order to obtain a putative TGF-beta antagonist. Biochemical studies revealed that TbetaRIIs-Fc shared the same properties as the wild-type receptor. The TbetaRIIs-Fc receptor displayed an affinity of 1370 +/- 363 pM which was similar to those of the wild-type TbetaRII 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-beta1 and TGF-beta3 were able to bind TbetaBRIIs-Fc, TGF-beta2 could not compete with the binding of TGF-beta1 to TbetaRIIs-Fc. It was noted that this type of fused Fc receptor could be used in FlashPlate screening for potent agonism and antagonism of TGFbeta. Moreover, biological activities of the chimeric receptor showed it to be a potent TGF-beta1-antiproliferative and TGF-beta1-extracellular matrix transcriptional inhibitor on responses in Mv1Lu cells. To conclude, our results clearly show that the TbetaRIIs-Fc chimeric receptor could be used as a potent TGF-beta antagonist. These data raised the possibility that this TbetaRIIs-Fc construct might act successfully as an antagonist of both TGF-beta1 and TGF-beta3 in vivo.
Komesli
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Département d'Immunologie, Laboratoires Fournier S.A., Daix, France. s.komesli@fournier.fr
Vivien
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Dutartre
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D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D017931:DNA Primers; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics*; D007457:Iodine Radioisotopes; D011485:Protein Binding; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D012995:Solubility; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
D017931:DNA Primers; D007141:Immunoglobulin Fc Fragments; D007457:Iodine Radioisotopes; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta