Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated.
Transforming growth factor beta 1 (TGF beta 1)-null mice die fro complications due to an early-onset multifocal inflammatory disorder. We show here that cardiac cells are hyperproliferative and that intercellular adhesion molecule 1 (ICAM-1) is elevated. To determine which phenotypes are primarily caused by a deficiency in TGF beta 1 from those that are secondary to inflammation, we applied immunosuppressive therapy and genetic combination with the severe combined immunodeficiency (SCID) mutation to inhibit the inflammatory response. Treatment with antibodies to the leukocyte function-associated antigen 1 doubled longevity, reduced inflammation, and delayed heart cell proliferation. TGF beta 1-null SCID mice displayed no inflammation or cardiac cell proliferation, survived to adulthood, and exhibited normal major histocompatibility complex II (MHC II) and ICAM-1 levels. TGF beta 1-null pups born to a TGF beta 1-null SCID mother presented no gross congenital heart defects, indicating that TGF beta 1 alone does not play an essential role in heart development. These results indicate that lymphocytes are essential for the inflammatory response, cardiac cell proliferation, and elevated MHC II and ICAM-1 expression, revealing a vital role for TGF beta 1 in regulating lymphocyte proliferation and activation, which contribute to the maintenance of self tolerance.
Diebold
R J
RJ
Department of Molecular Genetics, University of Cincinnati College of Medicine, OH 45267, USA.
Eis
M J
MJ
Yin
M
M
Ormsby
I
I
Boivin
G P
GP
Darrow
B J
BJ
Saffitz
J E
JE
Doetschman
T
T
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000627:therapeutic use; D001483:Base Sequence; D018845:CD11 Antigens / Q000276:immunology*; D017931:DNA Primers; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D007167:Immunotherapy; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D007958:Leukocyte Count; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D016133:Polymerase Chain Reaction; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D016212:Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics*
D000906:Antibodies; D018845:CD11 Antigens; D017931:DNA Primers; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016212:Transforming Growth Factor beta