TNF-α and Th2 Cytokines Induce Atopic Dermatitis–Like Features on Epidermal Differentiation Proteins and Stratum Corneum Lipids in Human Skin Equivalents

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease in which the skin barrier function is disrupted. In this inflammatory AD environment, cytokines are upregulated, but the cytokine effect on the AD skin barrier is not fully understood. We aimed to investigate the influence of Th2 (IL-4, IL-13, IL-31) and pro-inflammatory (tumor necrosis factor alpha (TNF-α)) cytokines on epidermal morphogenesis, proliferation, differentiation, and stratum corneum lipid properties. For this purpose, we used the Leiden epidermal model (LEM) in which the medium was supplemented with these cytokines. Our results show that IL-4, IL-13, IL-31, and TNF-α induce spongiosis, augment TSLP secretion by keratinocytes, and alter early and terminal differentiation-protein expression in LEMs. TNF-α alone or in combination with Th2 cytokines decreases the level of long chain free fatty acids (FFAs) and ester linked ω-hydroxy (EO) ceramides, consequently affecting the lipid organization. IL-31 increases long chain FFAs in LEMs but decreases relative abundance of EO ceramides. These findings clearly show that supplementation with TNF-α and Th2 cytokines influence epidermal morphogenesis and barrier function. As a result, these LEMs show similar characteristics as found in AD skin and can be used as an excellent tool for screening formulations and drugs for the treatment of AD.

Stratum Corneum Tape Stripping: Monitoring of Inflammatory Mediators in Atopic Dermatitis Patients Using Topical Therapy

“…This was consistent with a significant decrease in the levels of various inflammatory mediators, mainly Th2-related cytokines and chemokines characteristic of acute AD lesions [23,24,25,26], including IL-4, IL-13, CCL2, CCL22, and CCL17. As expected, the levels of most inflammatory mediators were significantly higher in AD patients (before and after therapy) than in the healthy control group [7].…”

The role of emollients in pathogenetic therapy of atopic dermatitis in children

“…Так, было продемонстрировано в экспериментальных условиях [10,12] и в клинической практике [15,33], что при атопическом воспалении цито-кины Th2-профиля могут ингибировать гены терминаль-ной дифференцировки липидов кожного барьера (напри-мер, филаггрина). Установлено, что Th1-цитокины (фактор некроза опухоли альфа, интерферон-гамма) индуцируют синтез керамидов кожного барьера, необходимых для правильного функционирования эпидермального барьера, в то время как Th2-цитокины (IL-4), наоборот, ингибируют их выработку [18,32].…”

Atopic Dermatitis: Collegium Internationale Allergologicum (CIA) Update 2019

“…A deficiency of filaggrin might affect the differentiation of keratinocytes [59], the expression of tight junction proteins [60], endogenous protease activity [61], and TSLP production [62]. Other factors that have been associated with a defective epidermal barrier in AD are an altered lipid organization and ceramide composition with an increase in the proportion of short-chain ceramides in the context of Th2 inflammation [63-66]. Furthermore, an imbalance of protease inhibitors, e.g., reduced LEKTI expression, and proteases resulting in a high activity of both endogenous and exogenous proteases with subsequent PAR 2 activation and increased TSLP production, is thought to contribute to AD pathogenesis [67-70].…”