Abstract
TGF-β1 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-β1, we generated mice with endocrine expression of active TGF-β1 on a TGF-β1 null background (TGF-β1 (-/-/TG)) by crossing TGF-β1 (+/-) mice with transgenic mice (TG) that express recombinant TGF-β1 specifically in the liver and secrete it in the blood. The TGF-β1 (-/-/TG) mice exhibit a survival profile similar to the TGF-β1 (-/-) mice indicating a failure to rescue the lethal phenotype. However, serum TGF-β1 levels in the TGF-β1 (-/-/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-β1 (-/-) mice, the TGF-β1 (-/-/TG) mice have glomerulonephritis in their kidneys similar to the TG mice. Thus, the phenotype of TGF-β1 (-/-/TG) animal model indicates the potential role of circulating active-TGF-β1 in reducing inflammation, but its failure to rescue lethality in TGF-β1 null mice indicates a critical autocrine role of TGF-β1.
| Original language | English |
|---|---|
| Pages (from-to) | 43-50 |
| Number of pages | 8 |
| Journal | Cytokine |
| Volume | 18 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2002 |
Bibliographical note
Funding Information:From the 1Functional Genomics Unit and Gene Targeting Facility, National Institute of Dental and Craniofacial Research, 2Labora-tory of Immunology, National Eye Institute, 3Laboratory of Cell Regulation and Carcinogenesis, and 4Laboratory of Experimen-tal Carcinogenesis, National Cancer Institute, 5Veterinary Resources Program, Office of the Director, National Institutes of Health, Bethesda, MD 20892; 6Veterinary and Tumor Pathology Section, Office of Laboratory Science, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, 7Depart-ment of Radiation Medicine, University of Kentucky, Lexington, KY 40536 Correspondence to: Ashok B. Kulkarni, Ph.D., National Institutes of Health, Building 30, Room 529, Bethesda, MD 20892. E-mail: [email protected] Received 23 November 2001; accepted in revised form 24 February 2002; accepted for publication 28 February 2002 1043–4666/02/$-see front matter 2002 Elsevier Science Ltd.
Funding
From the 1Functional Genomics Unit and Gene Targeting Facility, National Institute of Dental and Craniofacial Research, 2Labora-tory of Immunology, National Eye Institute, 3Laboratory of Cell Regulation and Carcinogenesis, and 4Laboratory of Experimen-tal Carcinogenesis, National Cancer Institute, 5Veterinary Resources Program, Office of the Director, National Institutes of Health, Bethesda, MD 20892; 6Veterinary and Tumor Pathology Section, Office of Laboratory Science, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, 7Depart-ment of Radiation Medicine, University of Kentucky, Lexington, KY 40536 Correspondence to: Ashok B. Kulkarni, Ph.D., National Institutes of Health, Building 30, Room 529, Bethesda, MD 20892. E-mail: [email protected] Received 23 November 2001; accepted in revised form 24 February 2002; accepted for publication 28 February 2002 1043–4666/02/$-see front matter 2002 Elsevier Science Ltd.
| Funders | Funder number |
|---|---|
| National Institutes of Health (NIH) | |
| National Eye Institute (NEI) | 3Laboratory |
| National Childhood Cancer Registry – National Cancer Institute | |
| National Institute of Dental and Craniofacial Research | 2Labora-tory |
| Office of the Director | |
| University of Kentucky |
Keywords
- Autoimmunity
- Cytokine therapy
- Glomerulonephritis
- Inflammation
- TGF-β1
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Biochemistry
- Hematology
- Molecular Biology