Effects of IL-4 on Conjunctival Fibroblasts: Possible Role in Ocular Cicatricial Pemphigoid

Ahmed, Babar; Foster, C. Stephen; Ahmed, A. Razzaque

doi:10.1167/iovs.02-1084

Cited by 36 publications

(26 citation statements)

References 42 publications

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“…Using human embryonic lung fibroblasts, it has been shown that both TGF-␤ 1 and IL-␤ 1 could induce trimer formation of heat shock transcription factor 1, which then bound to heat shock element of HSP47, resulting in increased expression of HSP47 [50]. In addition, certain other profibrogenic cytokines, including IL-4, IL-13, and connective tissue growth factor have shown to induce the expression of HSP47 [51][52][53]. Human conjunctival fibroblasts, treated with various concentrations of IL-4 [51] and IL-13 [52], could induce the expression of both HSP47 and collagens.…”

Section: Regulatory Mechanisms Of Hsp47 Expressionmentioning

confidence: 99%

Heat Shock Protein 47 and Renal Fibrogenesis

Taguchi

2005

Contributions to Nephrology

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Recent research has greatly increased our knowledge regarding the molecular mechanisms of collagen synthesis and processing. Heat specific shock protein (HSP47) is a collagen-specific molecular chaperone, and helps in post-translational modifications of procollagens, during biosynthesis of collagen. Both in vivo and in vitro studies have convincingly demonstrated that HSP47 is localized in the endoplasmic reticulum of collagen-producing cells, and that its synthesis is closely associated with the rate of procollagen assembly. Recent studies are directed towards the pathological relevance of HSP47 in tissue scarring, a process that is characterized by excessive accumulation of collagens. It appears likely that increased levels of HSP47 in fibrotic diseases assist in increased assembly of procollagen, and thereby help in excessive accumulation of collagens in the fibrotic mass. Such profibrotic effects of HSP47 suggest that modulation of HSP47 expression in scarring diseases might alter the course of fibrotic diseases. In this brief article, we review the role of HSP47 in renal fibrotic diseases and its relevance to other scarring diseases.

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Section: Regulatory Mechanisms Of Hsp47 Expressionmentioning

confidence: 99%

Heat Shock Protein 47 and Renal Fibrogenesis

Taguchi

2005

Contributions to Nephrology

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“…4,5 These processes involve a variety of cells, signals, and soluble extracellular factors, 4 including TGF-b, platelet-derived growth factor (PDGF), TNF-a, epidermal growth factor, insulin-like growth factor (IGF)-1, interleukin (IL)-1, IL-6, IL-4, interferons, BFGF, and macrophage-colony stimulating factor (m-CSF). 4,[6][7][8] TGF-b is one of the most important profibrogenic cytokines in the proliferative phase of wound healing. TGF-b induces the differentiation of fibroblasts into myofibroblasts, which are characterized by the expression of a-smooth muscle actin (a-SMA), a high contractile capacity, and the synthesis of extracellular matrix (ECM).…”

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confidence: 99%

YAP/TAZ Are Essential for TGF-β2–Mediated Conjunctival Fibrosis

Futakuchi

Inoue

Wei

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To investigate the roles of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), the major effector molecules of the Hippo pathway, in TGFb2-mediated conjunctival fibrosis.METHODS. Primary human conjunctival fibroblasts were treated with TGF-b2. The expression of YAP/TAZ was examined by Western blot analyses and immunocytochemistry. The expression of fibrotic proteins and genes were evaluated by Western blot analyses and quantitative real-time PCR, respectively. The effects of YAP/TAZ on fibrotic changes were examined by knockdown experiments and the YAP/TAZ inhibitor, verteporfin.RESULTS. TGF-b2 stabilized YAP/TAZ and subsequently activated Smad2/3, which led to the transcription of fibrotic genes in human primary conjunctival fibroblasts. These fibrotic genes were differently regulated by YAP/TAZ. Notably, a-smooth muscle actin, fibronectin, collagen I, and collagen IV were primarily regulated by YAP. In contrast, CCN family proteins (CTGF and CYR61) depended on both YAP and TAZ. Mechanistically, YAP/TAZ were located in close proximity to Smad2/3, and in particular, YAP was required for TGF-b2-mediated phosphorylation and the nuclear translocation of Smad2/3. Furthermore, a YAP/TAZ inhibitor markedly suppressed TGF-b2-mediated fibrotic changes in conjunctival fibroblasts.CONCLUSIONS. YAP/TAZ acted as a molecular hub of TGF-b2 signaling in a cellular model of conjunctival fibrosis. Moreover, verteporfin, a YAP/TAZ inhibitor exerted potent antifibrosis effects by suppressing TGF-b2-YAP/TAZ-Smad signaling. Our study highlights YAP/TAZ as essential regulators of conjunctival fibrosis and shows that inhibition of YAP/TAZ might potentially improve the outcomes of glaucoma filtration surgery.

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“…In pemphigoid diseases, the release of some proteolytic enzymes, involved in blistering formation, was highly correlated with a set of immunoregulatory cytokines [31]; high levels of IL-4, IL-5, IL-10, IL-13, IL-17 and IFN-γ have been detected in skin lesions or sera of patients with bullous pemphigoid and especially regarding IL-4 and IL-13 for ocular cicatricial pemphigoid and for oral mucous membrane pemphigoid, confirming their presumed involvement in the cicatricial scarring process [32][33][34]. IL-13 promoted both fibroblast migration and up-regulation of the expression for major histocompatibility complex components (HLA) and for some CD proteins, so that fibroblasts may perpetuate chronic inflammation and continue fibrosis [33].…”

Section: Experimental Evidence Of the Involvement Of Upper Cluster Gementioning

confidence: 72%