TRANSFORMING GROWTH FACTOR-BETA-1 NULL MUTATION IN MICE CAUSES EXCESSIVE INFLAMMATORY RESPONSE AND EARLY DEATH

To delineate specific developmental roles of transforming growth factor beta1 (TGF-beta1) we have disrupted its cognate gene in mouse embryonic stem cells by homologous recombination to generate TGF-beta1 null mice. These mice do not produce detectable amounts of either TGF-beta1 RNA or protein. After normal growth for the first 2 weeks they develop a rapid wasting syndrome and die by 3-4 weeks of age. Pathological examination revealed an excessive inflammatory response with massive infiltration of lymphocytes and macrophages in many organs, but primarily in heart and lungs. Many lesions resembled those found in autoimmune disorders, graft-vs.-host disease, or certain viral diseases. This phenotype suggests a prominent role for TGF-beta1 in homeostatic regulation of immune cell proliferation and extravasation into tissues.