The Inhibitory Effects of Transforming Growth Factor-Beta-1 (TGF-β1) in Autoimmune Diseases

Prud’homme, Gérald J.; Piccirillo, Ciriaco A.

doi:10.1006/jaut.1999.0339

Cited by 252 publications

(185 citation statements)

References 218 publications

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“…2 TGF-b1 is produced by all the major cell types participating in wound repair, including T-lymphocytes, macrophages, smooth muscle cells, endothelial cells, fibroblasts, epithelial cells and fibrocytes. 41,42 Fibroblasts are the predominant cell type involved in healing wounds and may provide much of the Deep dermal fibroblasts dictate HTS J Wang et al TGF-b1 in an active HTS, especially as its synthesis can be auto-induced in these cells. 43 We have previously reported that fibroblasts from HTS produce significant amount of TGF-b protein compared to fibroblasts from paired normal fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Deep dermal fibroblasts contribute to hypertrophic scarring

Wang

Dodd

Shankowsky

et al. 2008

Laboratory Investigation

182

137

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Hypertrophic scar (HTS) following thermal injury is a dermal fibroproliferative disorder that leads to considerable morbidity. The development of HTS involves numerous cell types and cytokines with dermal fibroblasts being a key cell. We have previously reported that the phenotype of fibroblasts isolated from HTS was altered compared to fibroblasts from normal skin. In this study, normal skin was horizontally sectioned into five layers using a dermatome from which fibroblasts were isolated and cultured. Cells from the deeper layers were observed to proliferate at a slow rate, but were morphologically larger. In ELISA and FACS assays, cells from the deeper layers produced more TGF-b1 and TGF-b1 producing cells were higher. In quantitative RT-PCR, the cells from the deeper layers had higher CTGF and HSP47 mRNA levels compared to those from superficial layers. In western blot, FACS and collagen gel assays, fibroblasts from the deeper layers produced more a-smooth muscle actin (a-SMA), had higher a-SMA positive cells and contracted collagen gels more. Fibroblasts from the deeper layers were also found to produce more collagen, but less collagenase by mass spectrometry and collagenase assay. Interestingly, cells from the deeper layers also produced more of the proteoglycan, versican, but less decorin. Taken together, these data strongly demonstrate that fibroblasts from the deeper layers of the dermis resemble HTS fibroblasts, suggesting that the deeper layer fibroblasts may be critical in the formation of HTS. Hypertrophic scarring is a common fibroproliferative disorder of the human dermis characterized by erythematous, raised, pruritic lesions of the healing skin, which is usually following thermal and other injuries that involve the deep dermis. 1 These lesions lead to scarring that compromises the appearance of healing skin and are commonly associated with contractures that limit movement and function of involved joints and facial features. As such, HTS is the principal factor that contributes to the prolonged and often uncomfortable rehabilitation period for thermally injured patients, particularly those who have survived large lifethreatening injuries, children, and individuals of dark-skinned races, in whom such scarring occurs more commonly. 2 The undesirable physical properties of HTS tissue can be attributed to the presence of a large amount of extracellular matrix that is of altered composition and organization, compared to normal dermis or mature scar. This matrix is the product of a dense population of fibroblasts, maintained in a hyperactive state by inflammatory cytokines such as TGF-b and other factors, some of which may be physical in origin. 3 Although the molecular and cellular events that lead to HTS have been extensively studied, the pathogenesis of this condition is still not well understood, making treatment difficult.Key cells involved in HTS are the dermal fibroblasts. Dermal fibroblasts are a dynamic and diverse population of cells whose function in skin and HTS in many respects remain unkn...

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Section: Discussionmentioning

confidence: 99%

Deep dermal fibroblasts contribute to hypertrophic scarring

Wang

Dodd

Shankowsky

et al. 2008

Laboratory Investigation

182

137

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“…Thymectomy of neonatal mice in the first week of life, but not on the day of birth or 7 days after birth, results in the development of autoimmune disease, which can be reversed by adoptive transfer of either thymocytes from neonates or lymphocytes from spleen and lymph nodes of adult mice (58,64). Suppressor and regulatory T cells secrete TGF-␤1 (21,22). Since TGF-␤1 is produced in the thymus and is secreted by both suppressor and regulatory T cells, depletion of TGF-␤1 with Ab reverses the regulatory function of CD4 ϩ CD25 ϩ T cells and makes them proliferate in response to mitogenic stimuli (65).…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Regulates Lymphocyte Homeostasis by Preventing Activation and Subsequent Apoptosis of Peripheral Lymphocytes

Bommireddy¹,

Saxena²,

Ormsby³

et al. 2003

The Journal of Immunology

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TGF-β1 plays an important role in the maintenance of immune homeostasis and self-tolerance. To determine the mechanism by which TGF-β1 prevents autoimmunity we have analyzed T cell activation in splenic lymphocytes from TGF-β1-deficient mice. Here we demonstrate that unlike wild-type splenic lymphocytes, those from Tgfb1−/− mice are hyporesponsive to receptor-mediated mitogenic stimulation, as evidenced by diminished proliferation and reduced IL-2 production. However, they have elevated levels of IFN-γ and eventually undergo apoptosis. Receptor-independent stimulation of Tgfb1−/− T cells by PMA plus ionomycin induces IL-2 production and mitogenic response, and it rescues them from anergy. Tgfb1−/− T cells display decreased CD3 expression; increased expression of the activation markers LFA-1, CD69, and CD122; and increased cell size, all of which indicate prior activation. Consistently, mutant CD4+ T cells have elevated intracellular Ca2+ levels. However, upon subsequent stimulation in vitro, increases in Ca2+ levels are less than those in wild-type cells. This is also consistent with the anergic phenotype. Together, these results demonstrate that the ex vivo proliferative hyporesponsiveness of Tgfb1−/− splenic lymphocytes is due to prior in vivo activation of T cells resulting from deregulated intracellular Ca2+ levels.

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“…There is a vast literature on the immunobiology of TGF-b, 124 and only major points are mentioned here. At least three TGF-b isoforms exist in mammals, but TGF-b1 is the principal type produced by cells of the immune system.…”

Section: Tgf-b1 a Potent Anti-inflammatory Cytokinementioning

confidence: 99%

“…Thus, cytokines that are generally thought of as anti-inflammatory, such as TGF-b1, sometimes have inflammatory effects. 124 Similarly, proinflammatory cytokines, such as IL-12, are sometimes, paradoxically, protective. For instance, Hagiwara and colleagues found that administering a DNA plasmid encoding IL-12 to MRL lpr/lpr mice significantly inhibited lymphadenopathy and splenomegaly.…”

Section: Anti-inflammatory Cytokine Gene Therapymentioning

confidence: 99%