Endocrine expression of the active form of TGF-beta1 in the TGF-beta1 null mice fails to ameliorate lethal phenotype.
TGF-beta1 null mice die by 3 to 4 weeks of age due to a severe autoimmune-mediated multifocal inflammation resulting in multi-organ failure. To assess the therapeutic potential of circulating levels of active TGF-beta1, we generated mice with endocrine expression of active TGF-beta1 on a TGF-beta1 null background (TGF-beta1 (-/-/TG)) by crossing TGF-beta1(+/-) mice with transgenic mice (TG) that express recombinant TGF-beta1 specifically in the liver and secrete it in the blood. The TGF-beta1 (-/-/TG) mice exhibit a survival profile similar to the TGF-beta1 (-/-) mice indicating a failure to rescue the lethal phenotype. However, serum TGF-beta1 levels in the TGF-beta1 (-/-/TG) mice were restored to near normal levels with expression in all the tissues, notably in the kidney and spleen. Histopathology showed reduced inflammation in the target tissues, especially in the heart. Interestingly, unlike TGF-beta1 (-/-) mice, the TGF-beta1 (-/-/TG) mice have glomerulonephritis in their kidneys similar to the TG mice. Thus, the phenotype of TGF-beta1 (-/-/TG) animal model indicates the potential role of circulating active-TGF-beta1 in reducing inflammation, but its failure to rescue lethality in TGF-beta1 null mice indicates a critical autocrine role of TGF-beta1.
Longenecker
Glenn
G
Functional Genomics Unit and Gene Targeting Facility, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA.
Thyagarajan
Tamizchelvi
T
Nagineni
Chandrasekharam N
CN
Flanders
Kathleen C
KC
Factor
Valentina
V
Miller
Georgina
G
Ward
Jerrold M
JM
Nalca
Aysegul
A
Rangnekar
Vivek M
VM
Thorgeirsson
Snorri
S
Kulkarni
Ashok B
AB
D000818:Animals; D001835:Body Weight; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004703:Endocrine System / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D005921:Glomerulonephritis / Q000209:etiology / Q000235:genetics; D006579:Heterozygote; D007249:Inflammation; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D010641:Phenotype; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1