The mouse tight skin ( Tsk ) phenotype is not dependent on the presence of mature T and B lymphocytes

Siracusa, Linda D.; McGrath, Rodney; Fisher, Jill K.; Jimenez, Sergio A.

doi:10.1007/s003359900894

Cited by 31 publications

(23 citation statements)

References 21 publications

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“…On the one hand, blocking IL-4 with neutralizing antibodies or by genetic targeting prevented scleroderma-like skin induration in Tsk1/+ mouse, a heritable model of skin fibrosis associated with a fibrillin-1 mutation [18,19] . Other studies, however, indicated that the tight skin phenotype was independent of T or B lymphocytes, consistent with the notion that the cutaneous pathology in TSK mice reflected an immunity-independent fibrotic process [20][21][22] . Skin fibrosis in mice induced by bleomycin injection is a useful animal model for investigating the fibrotic response in human scleroderma.…”

mentioning

confidence: 71%

Increased Bleomycin-Induced Skin Fibrosis in Mice Lacking the Th1-Specific Transcription Factor T-bet

Lakos

Melichian

et al. 2006

Pathobiology

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Fibrosis, the pathological hallmark of scleroderma and related conditions, is due to sustained activation of tissue fibroblasts. Accumulating evidence implicates cytokine networks in initiating, and propagating or terminating fibroblast activation, and the specific cytokine phenotype dictates evolution of the fibrotic response toward either resolution or scarring. In particular, cytokines that promote fibroblast proliferation and myofibroblast differentiation and extracellular matrix (ECM) accumulation functionally define a type 2 (Th2) immune response, whereas interferon-γ, which suppresses diverse fibroblast activities, defines a type 1 (Th1) immune response. It remains unclear what role the balance between Th1 and Th2 cytokines plays in the pathogenesis of fibrosis. Here we used bleomycin-induced skin fibrosis as a murine model for human scleroderma in order to study the fibrotic response in mice lacking T-bet, a transcription factor that is essential for initiating Th1 lineage development of CD4+ T lymphocytes. Spleen cells from T-bet null (T-bet^–/–) mice exhibited a typical Th2 cytokine profile ex vivo, with elevated production of interleukin-4 (IL-4), IL-5 and IL-13, and diminished production of interferon-γ. Bleomycin-induced early mast cells and eosinophil accumulation, and eosinophil degranulation, in the lesional tissue were greater in T-bet^–/– mice than in wild-type control mice. At a later time point, T-bet^–/– mice developed significantly more extensive dermal and especially hypodermal fibrosis. Elevated TGF-β expression and intracellular Smad activation were prominent in lesional skin. Infiltrating eosinophils appeared to be an important cellular source of TGF-β. These results demonstrate that in mice lacking T-bet bleomycin induced exaggerated skin fibrosis, suggesting that T-bet has an important physiologic role in regulation of tissue repair by promoting Th1 immune responses that prevent excessive ECM accumulation.

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mentioning

confidence: 71%

Increased Bleomycin-Induced Skin Fibrosis in Mice Lacking the Th1-Specific Transcription Factor T-bet

Lakos

Melichian

et al. 2006

Pathobiology

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“…The simplest explanation for these results is that IL-4 produced by T cells plays a critical role in the skin manifestations of the scleroderma-like syndrome of TSK mice. By contrast, Siracusa et al (24) reported that the disruption of the Rag2 gene does not influence the length of stretchable skin in TSK mice. It was proven that the generation of TSK͞ϩ, Rag2Ϫ͞Ϫmice was difficult, because both TSK and Rag2 genes are on chromosome 2, Ϸ6.5 cM apart.…”

Section: Discussionmentioning

confidence: 98%

Disrupting the IL-4 gene rescues mice homozygous for the tight-skin mutation from embryonic death and diminishes TGF-β production by fibroblasts

Kodera

McGaha

Phelps

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

104

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The TSK͞TSK mutation is embryonic lethal; embryos have been reported to die at 7-8 days of gestational age. Crossing TSK͞؉, IL-4؉͞؊ mice revealed that disrupting one or both IL-4 alleles allowed survival of 29 and 47%, respectively, of TSK͞TSK mice. These mice failed to develop cutaneous hyperplasia but did exhibit the emphysema that is found in TSK͞؉ mice. We showed that IL-4 stimulation of fibroblasts increased the level of transforming growth factor-␤ (TGF-␤) mRNA and that lungs of TSK͞؉, IL-4؊͞؊ mice had substantially less TGF-␤ mRNA than lungs of TSK͞؉, IL-4؉͞؉ mice. Thus IL-4 seems to regulate the expression of TGF-␤ in fibroblasts, providing an explanation for the absence of cutaneous hyperplasia in TSK͞؉, IL-4R␣؊͞؊ and TSK͞؉, TGF-␤؉͞؊ mice.

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“…Kasturi et al [22] showed that TSK/+J H D-/-mice devoid of mature B cells develop cutaneous hyperplasia. Recently, Siracusa et al [29] reported that TSK/+RAG2-/-mice developed cutaneous hyperplasia suggesting that mature T cells do not contribute to the pathogenesis. However, these results should be interpreted with caution, since TSK and RAG2 gene are located on chromosome 2.…”

Section: Introductionmentioning

confidence: 98%

Genetic and immunologic features associated with scleroderma-like syndrome of TSK mice

1999

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Tight-skin (TSK) mouse, the experimental model for scleroderma, develops cutaneous hyperplasia and autoantibodies to scleroderma specific autoantigens. TSK syndrome is caused by a mutation on chromosome 2. Induction of cutaneous hyperplasia is due to intragenic duplication of exons 17 to 40 of fibrillin-1 gene, mapping close to TSK locus. The mutant mouse expresses a 14kb Fbn transcript in addition to 11kb wild-type transcript. Immunoprecipation analysis confirms that the mutant transcript is functional and codes for a 420kD fibrillin. The occurrence of TSK syndrome is independent of the presence of mature lymphocytes although splenic/bone marrow cells appear to be capable of transferring the disease in normal animals. Transgenic mice expressing mutant transgene develop mild skin thickness with associate biochemical changes but do not develop anti-topo I antibodies. Among the other factors that may contribute to the develop- ment of hyperplasia, collagen V seems to play an important role.

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The mouse tight skin ( Tsk ) phenotype is not dependent on the presence of mature T and B lymphocytes

Cited by 31 publications

References 21 publications

Increased Bleomycin-Induced Skin Fibrosis in Mice Lacking the Th1-Specific Transcription Factor T-bet

Increased Bleomycin-Induced Skin Fibrosis in Mice Lacking the Th1-Specific Transcription Factor T-bet

Disrupting the IL-4 gene rescues mice homozygous for the tight-skin mutation from embryonic death and diminishes TGF-β production by fibroblasts

Genetic and immunologic features associated with scleroderma-like syndrome of TSK mice

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