Of the three TGF-beta isoforms, type 1 TGF-beta is both the most abundant in most tissues and the most acutely regulated in injury, repair, and the pathogenesis of various diseases. Although they lack any obvious developmental defects, mice in which the TGF-beta1 gene has been knocked out by targeted disruption die at about 3 weeks of age of multifocal inflammatory disease. This is accompanied by significantly elevated levels of nitric oxide in the serum of these mice. We have investigated the autoimmune phenotype in these mice and demonstrated, by backcrossing these mice onto an major histocompatibility antigen II null background, that generation of autoantibodies and tissue inflammation is dependent on expression of MHC class II antigen and the presence of CD4+ T-cells. This cross enhances effects of TGF-beta1 on hematopoiesis resulting in myeloproliferative disease with prominent extramedullary myeloplasia. In another approach, immunosuppressive treatments including rapamycin, dexamethasone, anti-CD4, and anti-CD8 are being used to prolong the life of the TGF-beta1 null mice. This has now made possible the study of wound healing in 4-5 week old mice in which maternally-transferred TGF-beta1 has been depleted. Finally, use of differential display showed that expression of ND2, a mitochondrially encoded component of the electron-transport chain, was suppressed in TGF-beta1 null mice. This has led to the demonstration that several mitochondrially-encoded components of this enzyme cascade are coordinately suppressed, a finding consistent with the observation of ultrastructural abnormalities in Golgi and mitochondria of cells of liver, heart, and lung of TGF-beta1 null mice which are strongly suggestive of an energy deficit and impaired vesicular transport. We have shown that treatment of either TGF-beta1 (-/-) and TGF-beta1 (+/+) cells with TGF-beta in vitro results in rapid upregulation of expression of mitochondrial genes. Present investigations are aimed at determining the mechanism whereby TGF-beta1 regulates expression of mitochondrial genes and its effects on cellular energetics.
