Upregulation of Interleukin-13 and Its Receptor in a Murine Model of Bleomycin-Induced Scleroderma

Matsushita, Mariko; Yamamoto, Toshiyuki; Nishioka, Kiyoshi

doi:10.1159/000082331

Cited by 41 publications

(28 citation statements)

References 61 publications

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“…In the skin of this mouse model, expression of IL-13R 2, but not IL-13R 1, was up-regulated [25]. Oxazolone-induced colitis also increased expression of IL-13R 2, but not that of IL-13R 1 [10••].…”

Section: Regulation Of Expression Of Il-13 Receptorsmentioning

confidence: 99%

IL-13 receptor isoforms: Breaking through the complexity

Tabata¹,

Hershey

2007

Curr Allergy Asthma Rep

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Interleukin (IL)-13 is an immunoregulatory cytokine secreted predominantly by activated T-helper type 2 (Th2) cells, and it has been identified as crucial in developing allergic inflammatory responses. Its diverse functions are mediated by a complex receptor system including IL-4 receptor alpha (IL-4Ralpha; CD124) and two other cognate cell surface proteins, IL-13Ralpha1 (CD213a1) and IL-13Ralpha2 (CD213a2). IL-13Ralpha1 forms a heterodimer with IL-4Ralpha that is a signaling IL-13 receptor. In contrast, IL-13Ralpha2 has been thought to be a decoy receptor due to its short cytoplasmic tail. IL-13Ralpha2 exists on the cell membrane, intracellularly, and in soluble form. Recent reports revealed that membrane IL-13Ralpha2 may have some signaling capabilities, and soluble IL-13Ralpha2 is a critical endogenous modulator for IL-13 responses. The receptor has more complicated functions than a simple decoy receptor. In this review, we describe the isoforms of IL-13Ralpha2 and discuss newly revealed functions of IL-13Ralpha2.

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Section: Regulation Of Expression Of Il-13 Receptorsmentioning

confidence: 99%

IL-13 receptor isoforms: Breaking through the complexity

Tabata¹,

Hershey

2007

Curr Allergy Asthma Rep

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“…Therefore, the ability of silica to induce TNF-␣, IL-13, and MCP-1, all reported to be major contributors to the development of pulmonary inflammation and fibrosis, was examined (21,22,26,(34)(35)(36)(37)(38). Figure 5 demonstrates that silica exposure dose-dependently increased TNF-␣, IL-13, and MCP-1.…”

Section: W-shmentioning

confidence: 99%

“…In addition, TNF receptor KO mice have been reported to have impaired responses to silica exposure, including development of silicosis which has been attributed to alterations in chemokine levels, including MCP-1 (32,38,40). IL-13 has been studied extensively as a major contributor to the development of pulmonary fibrosis in several different models (35,37,(41)(42)(43). Mouse BMMC produced significant quantities of IL-13 after silica exposure and may represent a major source of IL-13 in silica-induced pulmonary inflammation.…”

Section: W-shmentioning

confidence: 99%

Silica-Directed Mast Cell Activation Is Enhanced by Scavenger Receptors

Brown

Swindle

Kushnir-Sukhov

et al. 2007

Am J Respir Cell Mol Biol

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Inhalation of crystalline silica results in pulmonary fibrosis and silicosis. It has been suggested that mast cells play a role in these conditions. How mast cells would influence pathology is unknown. We thus explored mast cell interactions with silica in vitro and in B6.CgKit W-sh mast cell-deficient mice. B6.Cg-Kit W-sh mice did not develop inflammation or significant collagen deposition after instillation of silica, while C57Bl/6 wild-type mice did have these findings. Given this supporting evidence of a role for mast cells in the development of silicosis, we examined the ability of silica to activate mouse bone marrow-derived mast cells (BMMC), including degranulation (␤-hexosaminidase release); production of reactive oxygen species (ROS) and inflammatory mediators; and the effects of silica on Fc⑀RI-dependent activation. Silica did not induce mast cell degranulation. However, TNF-␣, IL-13, monocyte chemotactic protein-1, protease activity, and production of ROS were dose-dependently increased after silica exposure, and production was enhanced after Fc⑀RI stimulation. This mast cell activation was inhibited by anti-inflammatory compounds. As silica mediates some effects in macrophages through scavenger receptors (SRs), we first determined that mast cells express scavenger receptors; then explored the involvement of SR-A and macrophage receptor with colleagenous structure (MARCO). Silica-induced ROS formation, apoptosis, and TNF-␣ production were reduced in BMMC obtained from SR-A, MARCO, and SR-A/MARCO knockout mice. These findings demonstrate that silica directs mast cell production of inflammatory mediators, in part through SRs, providing insight into critical events in the pathogenesis and potential therapeutic targets in silicosis. Keywords: B6.Cg-kitW-sh sash mouse; CD204; macrophage receptor with collagenous structure; mast cell; silicosis; SR-A Among environmental exposures that lead to pathologic changes in tissues is crystalline silica, which can result in occupational silicosis from inhalation of silica dusts in manufacturing, construction, farming, and mining operations. Silicosis, for which there is no effective treatment, leads to decreased pulmonary function and increased susceptibility to diseases of the respiratory tract (1, 2).Involvement of mast cells in silica-induced pulmonary inflammation has been suggested by two clinical observations. First, the number of mast cells within the lungs of individuals exposed to silica dust is increased (3). Second, an increase in mast cells staining for basic fibroblast growth factor located within silicotic nodules has been reported in lung sections obtained from patients with silicosis (4). Despite the suggestive CLINICAL RELEVANCEThis study demonstrates a role for mast cells in silicosis and is the first study to examine direct effects of silica on mast cell biology. It provides evidence that treatment of silicosis should explore mast cells as a potential therapeutic target.evidence for a role of mast cells in the development of silicosis, there are ...

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“…The sequence of cutaneous histopathological changes closely resembles that described in patients with scleroderma [1] . Bleomycin-induced fibrosis in the mouse is associated with increased expression of IL-13 and its receptor [23] , and pretreatment of the mice with IFN-␥ ameliorated the response [24] . However, to date the role and relative contribution and balance of Th1 and Th2 cytokines in the development of fibrosis have not been examined in the bleomycin-induced model of scleroderma.…”

mentioning

confidence: 99%

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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Upregulation of Interleukin-13 and Its Receptor in a Murine Model of Bleomycin-Induced Scleroderma

Cited by 41 publications

References 61 publications

IL-13 receptor isoforms: Breaking through the complexity

IL-13 receptor isoforms: Breaking through the complexity

Silica-Directed Mast Cell Activation Is Enhanced by Scavenger Receptors

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

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