Transforming growth factor-β3 (TGF-β3) knock-in ameliorates inflammation due to TGF-β1 deficiency while promoting glucose tolerance.

Abstract

Three homologues of TGF-β exist in mammals as follows: TGF-β1, TGF-β2, and TGF-β3. All three proteins share high homology in their amino acid sequence, yet each TGF-β isoform has unique heterologous motifs that are highly conserved during evolution. Although these TGF-β proteins share similar properties in vitro, isoform-specific properties have been suggested through in vivo studies and by the unique phenotypes for each TGF-β knock-out mouse. To test our hypothesis that each of these homologues has nonredundant functions, and to identify such isoform-specific roles, we genetically exchanged the coding sequence of the mature TGF-β1 ligand with a sequence from TGF-β3 using targeted recombination to create chimeric TGF-β1/3 knock-in mice (TGF-β1(Lβ3/Lβ3)). In the TGF-β1(Lβ3/Lβ3) mouse, localization and activation still occur through the TGF-β1 latent associated peptide, but cell signaling is triggered through the TGF-β3 ligand that binds to TGF-β receptors. Unlike TGF-β1(-/-) mice, the TGF-β1(Lβ3/Lβ3) mice show neither embryonic lethality nor signs of multifocal inflammation, demonstrating that knock-in of the TGF-β3 ligand can prevent the vasculogenesis defects and autoimmunity associated with TGF-β1 deficiency. However, the TGF-β1(Lβ3/Lβ3) mice have a shortened life span and display tooth and bone defects, indicating that the TGF-β homologues are not completely interchangeable. Remarkably, the TGF-β1(Lβ3/Lβ3) mice display an improved metabolic phenotype with reduced body weight gain and enhanced glucose tolerance by induction of beneficial changes to the white adipose tissue compartment. These findings reveal both redundant and unique nonoverlapping functional diversity in TGF-β isoform signaling that has relevance to the design of therapeutics aimed at targeting the TGF-β pathway in human disease.

• Authors: Bradford E Hall, Umesh D Wankhade, Joanne E Konkel, Karthik Cherukuri, Chandrasekharam N Nagineni, Kathleen C Flanders, Praveen R Arany, Wanjun Chen, Sushil G Rane, Ashok B Kulkarni
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 44 Pg. 32074-92 (Nov 01 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 24056369 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Protein Isoforms
• Recombinant Fusion Proteins
• TGFB1 protein, human
• TGFB3 protein, human
• Tgfb1 protein, mouse
• Tgfb3 protein, mouse
• Transforming Growth Factor beta1
• Transforming Growth Factor beta3
• Glucose

Topics

• Animals
• COS Cells
• Chlorocebus aethiops
• Gene Knock-In Techniques
• Glucose (genetics, metabolism)
• Hep G2 Cells
• Humans
• Inflammation (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Neovascularization, Physiologic (physiology)
• Protein Isoforms (genetics, metabolism)
• Recombinant Fusion Proteins (genetics, metabolism)
• Signal Transduction (physiology)
• Swine
• Transforming Growth Factor beta1 (genetics, metabolism)
• Transforming Growth Factor beta3 (genetics, metabolism)