Kinoshita H, Takai T, Le TA et al.Cytokine milieu modulates release of thymic stromal lymphopoietin from human keratinocytes stimulated with double-stranded RNA. J Allergy Clin Immunol 123:179-186
Thymic stromal lymphopoietin (TSLP) plays a key role in allergic diseases, such as atopic dermatitis (AD) and asthma. TSLP is highly expressed by keratinocytes in skin lesions of patients with AD, but environmental triggers for its release from keratinocytes with endogenous factors are not well understood. Patients with AD, in whom allergic sensitization is already established, are susceptible to viral dissemination.
We investigated TSLP's release from primary human keratinocytes stimulated with a Toll-like receptor (TLR) 3 ligand, polyinosinic-polycytidylic acid, which mimics viral double-stranded RNA (dsRNA), and its modulation by cytokines.
Primary human keratinocytes were stimulated with TLR ligands, cytokines, or both. TSLP released into culture supernatants was measured by means of ELISA.
Stimulation of keratinocytes with dsRNA induced release of TSLP and upregulated gene expression of TSLP and other cytokines and chemokines. The release of TSLP was enhanced by the addition of IL-4, IL-13, and/or TNF-alpha. With or without the T(H)2/TNF cytokines, the dsRNA-induced release of TSLP was upregulated by IFN-alpha and IFN-beta and suppressed by IFN-gamma, TGF-beta, or IL-17.
The effect of the TLR3 ligand on keratinocytes suggests contribution of viral dsRNA to skin inflammations under the influence of a cytokine milieu. The results imply that viral dsRNA and a T(H)2 cytokine milieu might promote T(H)2-type inflammation through an induction of TSLP expression, suggesting that a vicious cycle exists between AD with T(H)2-type inflammation and viral infections and a possible blockade of this cycle by other cytokine milieus provided by cells, such as T(H)1, regulatory T, and T(H)17 cells.
Available from: Kotaro Sugimoto
- "In lesions of AD, keratinocytes reside around damaged cells, where dsRNA might downregulate ΔNp63. Previous studies have shown that cellular damage or treatment with TLR3 ligands induces the production of TSLP in keratinocytes , . Given that a transgenic mouse model of keratinocyte-specific overproduction of TSLP is very similar to the chronic eczematous lesions of AD , aberrant production of TSLP followed by cell damage and liberation of dsRNA might underlie the clinical state of AD. "
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ABSTRACT: In the skin lesions of atopic dermatitis (AD), keratinocytes release large quantities of thymic stromal lymphopoietin (TSLP), causing unfavorable inflammation along with skin damage. Nevertheless, how TSLP influences keratinocytes themselves is still unknown. In this study, we showed that ΔNp63, a p53-homologue, predominantly expressed in keratinocytes regulated the receptor complex of TSLP, which determines susceptibility to self-derived TSLP. Expression of TSLP receptors in skin tissues and keratinocytes was assessed by immunohistochemistry and quantitative RT-PCR, and in vitro studies were also performed to examine the functional relevance of ΔNp63 in the expression of TSLP receptors and the constituting autocrine and/or paracrine pathway of TSLP under the condition of stimuli to innate receptors sensing cell damage. The results showed that normal keratinocytes in the upper epidermis preferentially expressed TSLP receptors and conversely lacked ΔNp63, which has an inhibitory effect on the expression of TSLP receptors. Interestingly, the epidermis of AD lesions was found to abundantly contain keratinocytes with low or undetectable levels of ΔNp63 (ΔNp63lo/-). Moreover, in the absence of ΔNp63, keratinocytes readily presented TSLP and other cytokines by stimuli through Toll-like receptor 3 (TLR3). Together with the evidence that extrinsic TSLP itself augments TSLP production by keratinocytes without ΔNp63, the results indicate that ΔNp63lo/- keratinocytes generate TSLP through a putative autocrine and/or paracrine pathway upon TLR3 stimulation within AD lesions, since moieties of damaged cells and pathogens stimulate TLR3.
PLoS ONE 08/2014; 9(8):e105498. DOI:10.1371/journal.pone.0105498 · 3.23 Impact Factor
Available from: Henrik Wolff
- "Skin-barrier defect promotes easy entry to the pathogens, allergens, and other molecules (toxins, irritants, and pollutants) (Boguniewicz and Leung, 2011; Carmi-Levy et al., 2011). In AD skin, keratinocytes respond to environmental triggers and are able to produce a unique profile of proinflammatory and pro-T-helper type 2 (Th2) cytokines, including IL-33 (Smith, 2009) and TSLP (Kinoshita et al., 2009), and promote the Th2 inflammation. In the more chronic phase, Th1 type cytokines dominate over Th2 cytokines. "
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ABSTRACT: IL-33 is an inducer of proinflammatory and Th2 cytokines, which play an important role in atopic dermatitis and allergic asthma. ST2 is a specific receptor for IL-33 and is expressed on Th2 cells, eosinophils and mast cells. A murine model of atopic dermatitis was used to characterize the role of ST2 in allergen induced skin inflammation and allergic asthma. ST2(-/-) and WT mice were epicutaneously sensitized with ovalbumin and Staphylococcal enterotoxin B, and intranasally challenged with ovalbumin. ST2(-/-) mice exhibited increased production of IFNγ and increased number of CD8(+) T cells in the sensitized skin and in the airways compared with WT mice. The number of eosinophils was decreased, and Th2 cytokines were downregulated in the airways of epicutaneously sensitized ST2(-/-) mice compared with WT controls. However, dermal eosinophil numbers were as in WT, and the levels of Th2 cytokines were even elevated in the sensitized skin of ST2(-/-) mice. ST2(-/-) mice had elevated numbers of neutrophils and macrophages and increased levels of proinflammatory cytokines in the sensitized skin. The role of ST2 differs between different target tissues: ST2 is dispensable for the development of Th2 response in the sensitized skin, whereas it is a main inducer of Th2 cytokines in asthmatic airways.Journal of Investigative Dermatology accepted article preview online, 30 April 2013; doi:10.1038/jid.2013.195.
Journal of Investigative Dermatology 04/2013; 133(11). DOI:10.1038/jid.2013.195 · 7.22 Impact Factor
Available from: Franck Morel
- "It has been suggested that the increased expression of IL-4 and IL-13 in atopic dermatitis skin may explain the susceptibility to bacterial and viral skin infections by reducing antimicrobial peptide expression  . On the other hand, as TLR3 agonists , IL-4 or IL-13 synergizes with TNFα or IL-1β  to induce expression of thymic stromal lymphopoietin (TSLP) in keratinocytes and subsequently induces the maturation of CD11c + dendritic cells involved in allergic inflammation. Besides regulation of their production, IL-4 and IL-13 activities can be modified by differential expression of their receptors. "
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ABSTRACT: Cutaneous homeostasis and defenses are maintained by permanent cross-talk among particular epidermal keratinocytes and immune cells residing or recruited in the skin, through the production of cytokines. If required, a coordinated inflammatory response is triggered, relayed by specific cytokines. Due to numerous reasons, troubles in the resolution of this phenomenon could generate a cytokine-mediated vicious circle, promoting skin chronic inflammation, the most common being atopic dermatitis and psoriasis. In this paper, we discuss the biological effects of cytokine on keratinocytes, more particularly on specific or shared cytokines involved in atopic dermatitis or psoriasis. We report and discuss monolayer or 3D in vitro models of keratinocytes stimulated by specific sets of cytokines to mimic atopic dermatitis or psoriasis. IL-22, TNFa, IL-4, and IL-13 combination is able to mimic an "atopic dermatitis like" state. In psoriasis lesions, over expression of IL-17 is observed whereas IL-4 and IL-13 were not detected; the replacement of IL-4 and IL-13 by IL-17 from this mix is able to mimic in vitro a "psoriasis like" status on keratinocytes. We conclude that specific cytokine environment deregulation plays a central role on skin morphology and innate immunity, moving towards specific pathologies and opening the way to new therapeutic strategies.
Journal of Allergy 11/2012; 2012(6):718725. DOI:10.1155/2012/718725
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