Tacrolimus abrogates <scp>TGF</scp>‐β1‐induced type I collagen production in normal human fibroblasts through suppressing p38<scp>MAPK</scp> signalling pathway: implications on treatment of chronic atopic dermatitis lesions

Lan, C.‐C. E.; Fang, Ay-Huey; Wu, Ping; Wu, Ching‐Shuang

doi:10.1111/jdv.12086

Cited by 28 publications

(20 citation statements)

References 64 publications

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“…Interestingly, immunosuppressive peptidyl-prolyl isomerase inhibitors like FK506 have been ascribed potent antifibrotic effects in lung fibrosis (40)(41)(42)(43). FK506 suppresses collagen synthesis and expression of the TGF-b 1 receptor in dermal and lung fibroblasts, but the underlying mechanisms are largely unclear (41,44,45). Our findings put forward the possibility that inhibition of FKBP10 might contribute to the antifibrotic effects of FK506.…”

Section: Discussionmentioning

confidence: 78%

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Staab-Weijnitz

Fernandez

Knüppel

et al. 2015

Am J Respir Crit Care Med

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Rationale: Increased abundance and stiffness of the extracellular matrix, in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506-binding protein 10 (FKBP10) is a collagen chaperone, mutations of which have been indicated in the reduction of extracellular matrix stiffness (e.g., in osteogenesis imperfecta).Objectives: To assess the expression and function of FKBP10 in IPF. Methods:We assessed FKBP10 expression in bleomycininduced lung fibrosis (using quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunofluorescence), analyzed microarray data from 99 patients with IPF and 43 control subjects from a U.S. cohort, and performed Western blot analysis from 6 patients with IPF and 5 control subjects from a German cohort. Subcellular localization of FKBP10 was assessed by immunofluorescent stainings. The expression and function of FKBP10, as well as its regulation by endoplasmic reticulum stress or transforming growth factor-b 1 , was analyzed by small interfering RNA-mediated loss-of-function experiments, quantitative reverse transcriptase-polymerase chain reaction, Western blot, and quantification of secreted collagens in the lung and in primary human lung fibroblasts (phLF). Effects on collagen secretion were compared with those of the drugs nintedanib and pirfenidone, recently approved for IPF.Measurements and Main Results: FKBP10 expression was up-regulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68 1 macrophages. Transforming growth factor-b 1 , but not endoplasmic reticulum stress, induced FKBP10 expression in phLF. The small interfering RNA-mediated knockdown of FKBP10 attenuated expression of profibrotic mediators and effectors, including collagens I and V and a-smooth muscle actin, on the transcript and protein level. Importantly, loss of FKBP10 expression significantly suppressed collagen secretion by phLF.Conclusions: FKBP10 might be a novel drug target for IPF.

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Section: Discussionmentioning

confidence: 78%

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Staab-Weijnitz

Fernandez

Knüppel

et al. 2015

Am J Respir Crit Care Med

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“…Fibroblasts are the most common producers of collagen and are subject to complex autocrine and paracrine cytokine signals to regulate its formation, of which TGFβ is crucial [66, 67]. In combination with these cytokines there are a number of enzymes and proteins that through cleavage or binding can affect collagen turnover [68].…”

Section: Resultsmentioning

confidence: 99%

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

et al. 2017

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Keloid disease (KD) is a fibroproliferative cutaneous tumour characterised by heterogeneity, excess collagen deposition and aggressive local invasion. Lack of a validated animal model and resistance to a multitude of current therapies has resulted in unsatisfactory clinical outcomes of KD management. In order to address KD from a new perspective, we applied for the first time a site-specific in situ microdissection and gene expression profiling approach, through combined laser capture microdissection and transcriptomic array. The aim here was to analyse the utility of this approach compared with established methods of investigation, including whole tissue biopsy and monolayer cell culture techniques. This study was designed to approach KD from a hypothesis-free and compartment-specific angle, using state-of-the-art microdissection and gene expression profiling technology. We sought to characterise expression differences between specific keloid lesional sites and elucidate potential contributions of significantly dysregulated genes to mechanisms underlying keloid pathobiology, thus informing future explorative research into KD. Here, we highlight the advantages of our in situ microdissection strategy in generating expression data with improved sensitivity and accuracy over traditional methods. This methodological approach supports an active role for the epidermis in the pathogenesis of KD through identification of genes and upstream regulators implicated in epithelial-mesenchymal transition, inflammation and immune modulation. We describe dermal expression patterns crucial to collagen deposition that are associated with TGFβ-mediated signalling, which have not previously been examined in KD. Additionally, this study supports the previously proposed presence of a cancer-like stem cell population in KD and explores the possible contribution of gene dysregulation to the resistance of KD to conventional therapy. Through this innovative in situ microdissection gene profiling approach, we provide better-defined gene signatures of distinct KD regions, thereby addressing KD heterogeneity, facilitating differential diagnosis with other cutaneous fibroses via transcriptional fingerprinting, and highlighting key areas for future KD research.

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“…In AD, repeated scratching turns the erythematous acute lesions into lichenified chronic and intractable ones . The lichenified and thickened skin lesions are a result of epidermal acanthosis and dermal fibrosis . Lan et al demonstrated that tacrolimus significantly downregulated the proliferation of human fibroblasts and their production of collagen I, both of which were stimulated by transforming growth factor β‐1.…”

Section: Suppression Of Allergic Inflammation By Tacrolimusmentioning

confidence: 99%

“…The lichenified and thickened skin lesions are a result of epidermal acanthosis and dermal fibrosis . Lan et al demonstrated that tacrolimus significantly downregulated the proliferation of human fibroblasts and their production of collagen I, both of which were stimulated by transforming growth factor β‐1. Caproni et al quantified the profile of inflammatory cell infiltration in the lesional skin before and after treatment with topical tacrolimus and topical hydrocortisone butyrate.…”

Section: Suppression Of Allergic Inflammation By Tacrolimusmentioning

confidence: 99%

Mechanistic insights into topical tacrolimus for the treatment of atopic dermatitis

Nakahara

Morimoto

Murakami

et al. 2018

Pediatric Allergy Immunology

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More than 15 years have passed since the clinical launch of topical tacrolimus for the treatment of atopic dermatitis. Its efficacy and safety have been clearly demonstrated in many global and domestic short-term and long-term clinical trials. Although the prolonged external application of steroids causes many adverse reactions including cutaneous atrophy, no such reactions occur with the use of topical tacrolimus. Therefore, the therapeutic guidelines recommend a combined topical treatment with tacrolimus and steroids. Tacrolimus is a potent immunosuppressant. However, recent studies have revealed its diverse action on the cardinal pathomechanisms of atopic dermatitis. In this review, we summarize the mechanistic role of tacrolimus in various aspects of allergic inflammation including mast cell activation, innate allergic response, pruritus, sensory nerve activation, and skin barrier dysfunction.

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Tacrolimus abrogates TGF‐β1‐induced type I collagen production in normal human fibroblasts through suppressing p38MAPK signalling pathway: implications on treatment of chronic atopic dermatitis lesions

Cited by 28 publications

References 64 publications

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

Mechanistic insights into topical tacrolimus for the treatment of atopic dermatitis

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