Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable.
Recent studies in mouse models deficient in transforming growth factor beta (TGF-beta) signaling have documented TGF-beta as one of the major regulators of immune function. TGF-beta1-null animals demonstrated massive autoimmune inflammation affecting multiple organs, but attempts to transfer the phenotype to normal animals by bone marrow transplantation only resulted in minor inflammatory lesions. We wanted to ask whether a lethal inflammatory phenotype would develop following transplantation of bone marrow deficient for the TGF-beta type II receptor (TbetaRII) gene to normal recipient animals. The TbetaRII-null mutation would generate a cell autonomous phenotype that cannot be reverted by the influence of endocrine or paracrine TGF-beta derived from the recipient animal. We have generated conditional knockout mice in which the TbetaRII gene is disrupted upon induction with interferon-alphabeta or polyI:polyC. We show that induction of TbetaRII gene disruption in these mice by polyI:polyC results in a lethal inflammatory disease. Importantly, bone marrow from conditional knockout mice transferred to normal recipent mice caused a similar lethal inflammation, regardless of whether induction of TGF-beta receptor deficiency occurred in donor animals before, or in recipient animals after transplantation. These results show that TGF-beta signaling deficiency within cells of hematopoietic origin is sufficient to cause a lethal inflammatory disorder in mice. This animal model provides an important tool to further clarify the pathogenic mechanisms in animals deficient for TGF-beta signaling and the importance of TGF-beta to regulate immune functions.
Pubmed ID: 12091349 RIS Download
Animals | Antigens, Nuclear | Autoantibodies | Autoimmune Diseases | Bone Marrow Transplantation | Inflammation | Lymphocytes | Mice | Mice, Knockout | Nuclear Proteins | Poly I-C | Protein-Serine-Threonine Kinases | Receptors, Transforming Growth Factor beta | Signal Transduction | Transforming Growth Factor beta