STUDY OF MICE IN WHICH THE TGF BETA 1 GENE HAS BEEN DISRUPTED

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Transforming growth factor-beta (TGF-beta) has previously been implicated in embryonic development and in regulating both cell proliferation and expression of target genes. 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 and repair and in 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 possible initiating event in this inflammatory syndrome and found that, prior to detection of any tissue infiltrates, expression of both class I and II major histocompatibility (MHC) antigens is high in these mice while generally undetectable in comparable tissues in normal littermates, suggesting that TGF-beta may be a natural repressor of MHC antigen expression. We have now crossed the TGF-beta1 null mice with mice lacking the MHC class II gene and with nude mice, which lack T and B lymphocytes. The double MHC class II/TGF-beta1 knockouts show no tissue infiltrates, but die of myeloproliferative disease with prominent extramedullary hematopoiesis, underscoring the role of TGF-beta1 as a critical regulator of hematopoiesis. 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. These approaches are now providing new insights into possible links between TGF-beta and energy metabolism. Data suggest that expression of a gene highly homologous to a key mitochondrial enzyme, NADH dehydrogenase, is controlled by TGF-beta1, both in tissues and in cell lines derived from the TGF-beta1 knockout mice. Experiments with TGF-beta1 (-/-) hepatocyte cell lines demonstrate that TGF-beta1 plays a key role in regulation of energy-dependent cellular events and expression of this key mitochondrial enzyme.