Autoimmune manifestations in the transforming growth factor-beta 1 knockout mouse

Yaswen, Linda; Kulkarni, A. B.; Fredrickson, T. N.; Mittleman, Barbara; Schiffman, Rhett M.; Payne, Susan N.; Longenecker, Glenn; Mozes, Edna; Karlsson, Stefán

doi:10.1182/blood.v87.4.1439.bloodjournal8741439

Cited by 189 publications

(68 citation statements)

References 21 publications

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“…Interestingly, the glomerular lesions in MHC-I/IL-4 tg mice resembled the progressive renal disease observed in transforming growth factor-b1 (TGF-b1) tg mice which show elevated plasma TGF-b1 levels (Kopp et al 1996). However, the extrarenal autoimmune-type manifestations in MHC-I/IL-4 tg mice were similar to the disorders seen in TGF-b1 deficient mice which did not show any renal changes histologically despite immunohistochemical detection of glomerular immune deposits (Yaswen et al 1996). It has been well established that TGF-b exerts various effects, including immunosuppression and fibrogenesis, and acts in a context-dependent fashion (McCartney-Francis & Wahl 1994).…”

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confidence: 61%

“…This is supported by a report showing that intramuscular injection of TGF-b expression vectors into lupus prone mice (MRL/lpr/lpr) decreased autoantibodies to chromatin (Raz et al 1993). It is therefore not surprising that TGF-b deficient mice show similar autoimmune-features (Yaswen et al 1996) as MHC-I/IL-4 tg mice. These TGF-b1 deficient mice are not able to produce TGF-b1 by themselves, but they are not 0 protein knockouts', since TGF-b1 has been detected in several tissues, and has been shown to be derived from maternal sources through placenta and lactation (Letterio et al 1994).…”

Section: Discussionmentioning

confidence: 99%

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Progression of renal disease in interleukin‐4 transgenic mice: involvement of transforming growth factor‐β

Rüger

Hasan

Erb

et al. 1999

Int J Experimental Path

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Recent reports have suggested the involvement of interleukin-4 (IL-4) in glomerular pathophysiology. Using immunohistochemistry and reverse transcriptase polymerase chain reaction we investigated the renal lesions in transgenic (tg) mice with widely distributed IL-4 expression including the kidney, and measured the serum levels of the cytokines transforming growth factor-beta (TGF-beta) and IL-4 by ELISA. Transgenic animals exhibited glomerular hypertrophy with progressive mesangial sclerosis leading to renal failure. Renal IL-4 transcript expression, mesangial accumulation of collagen types I, III, IV and V, and immune deposition accompanied by increased expression of TGF-beta1 protein and mRNA were observed. Seven day-old transgenic animals showed early renal fibrotic changes in the absence of immune deposits or TGF-beta1 upregulation. The sera of transgenic mice not only showed elevated levels of circulating IL-4 (tg: 76.6 pg/ml +/- 7.1 vs wildtype (wt): < 3 pg/ml), but significantly decreased TGF-beta1 levels (tg: 18.9 ng/ml +/- 4.1 vs wt: 38.7 ng/ml +/- 2.9; P < 0.005). The disease severity correlated with the serum IL-4/TGF-beta1 ratio rather than with the IL-4 concentration. These data suggest that renal IL-4 production results in matrix accumulation prior to any immunological insult, that increased circulating IL-4/TGF-beta1 ratios are associated with renal immunopathological manifestations and that upregulation of renal TGF-beta1 expression following glomerular Ig deposition accelerates the sclerosis and exacerbates disease development.

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confidence: 61%

Section: Discussionmentioning

confidence: 99%

Progression of renal disease in interleukin‐4 transgenic mice: involvement of transforming growth factor‐β

Rüger

Hasan

Erb

et al. 1999

Int J Experimental Path

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“…Transgenic mice that overexpress TGF-â show increased extracellular laminin and fibronectin in their central nervous systems (144). In contrast, deletion of the TGF-â1 gene results in the death of 60% of mouse embryos, with the remainder exhibiting a multifocal inflammatory response (146). Thus, modulation of the TGF-â system to gain benefit is most likely to be achieved by other more subtle strategies.…”

Section: Anti-tgf-â Strategiesmentioning

confidence: 99%

Transforming Growth Factor‐β:A Promising Target for Anti‐Stenosis Therapy

Chamberlain

2001

Cardiovascular Drug Reviews

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Transforming growth factor-â (TGF-â) is the general name for a family of cytokines which have widespread effects on many aspects of growth and development. The TGF-â isoforms are produced by most cell types and exert a wide range of effects in a context-dependent autocrine, paracrine or endocrine fashion via interactions with distinct receptors on the cell surface. TGF-â is involved in the wound healing process and, thus plays a significant role in the formation of a restenotic lesion after percutaneous transluminal coronary angioplasty (PTCA) or stenting. Perhaps because of its wide-ranging effects, TGF-â is usually released from cells in a latent form, and its activation and signaling are complex. Manipulation of the TGF-â1, TGF-â2, and TGF-â3 isoforms by inhibiting their expression, activation, or signaling reduces scarring and fibrosis in animal models. However, to date, few have reached clinical trial. This review summarizes current knowledge on the activation and signaling of TGF-â, and focuses on the anti-TGF-â strategies which may lead to clinical applications in the prevention of restenosis following PTCA or stenting.

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“…In TGF-b1 knockout mice, animals die of a diffuse autoimmune response 3-4 weeks after birth. 7,8 Recently, the immune-regulatory role of BMPs has been emerging. Specifically, BMP-6 inhibits human B-cell progenitors and mature B cells 9,10 and has an antiproliferative effect on Jurkat Tag cells through up-regulation of the transcription factor, Id1.…”

Section: Introductionmentioning

confidence: 99%

Bone morphogenetic protein‐6 induces the expression of inducible nitric oxide synthase in macrophages

Kwon¹,

Lee²,

Lee³

et al. 2009

Immunology

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SummaryBone morphogenetic proteins (BMPs) are members of the transforming growth factor-b (TGF-b) superfamily. In the present study, we investigated the effect of BMPs on the production of inducible nitric oxide synthase (iNOS) in the murine macrophage cell line, RAW 264.7, and in mouse peritoneal macrophages. Among the BMPs, only BMP-6 induced iNOS expression in a time-dependent and dose-dependent manner in both cell types. Induction of iNOS was inhibited by both cycloheximide and actinomycin D, indicating that the induction of iNOS expression by BMP-6 requires new protein synthesis. Mechanistic studies revealed that the BMP-6-induced iNOS expression requires both Smads and nuclear factor-kappa B (NF-jB) signalling pathways. Furthermore, induction of interleukin-1b (IL-1b) was necessary for iNOS induction by BMP-6. These observations suggest that BMP-6 stimulates macrophages to produce iNOS through IL-1b via Smad and NF-jB signalling pathways and that BMP-6 may be an important regulator of macrophages.Keywords: bone morphogenetic proteins; interleukin-1b; inducible nitric oxide synthase; macrophages; nuclear factor-kappa B; Smads Please cite this article in press as: Kwon S. J. et al. Bone morphogenetic protein-6 induces the expression of inducible nitric oxide synthase in macrophages, Immunology (2009)

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Autoimmune manifestations in the transforming growth factor-beta 1 knockout mouse

Cited by 189 publications

References 21 publications

Progression of renal disease in interleukin‐4 transgenic mice: involvement of transforming growth factor‐β

Progression of renal disease in interleukin‐4 transgenic mice: involvement of transforming growth factor‐β

Transforming Growth Factor‐β:A Promising Target for Anti‐Stenosis Therapy

Bone morphogenetic protein‐6 induces the expression of inducible nitric oxide synthase in macrophages

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