Attenuated TGF‐β1 responsiveness of dendritic cells and their precursors in atopic dermatitis

Abstract

The responsiveness of DCs and their precursors to transforming growth factor beta1 (TGF-β1) affects the nature of differentiating DC subsets, which are essential for the severity of atopic dermatitis (AD). To evaluate TGF-β signaling in monocytes and monocytederived DCs of AD patients compared with that of controls, in vitro generated Langerhans cell (LC) like DCs, expression of TGF-β receptors, phospho-Smad2/3 and Smad7 were evaluated. Furthermore, TNF-α expression and synergistic effects of TNF-α upon TGF-β signaling and DC generation were evaluated. We found LC-like DC differentiation of monocytes from AD patients in response to TGF-β1 was remarkably reduced and TGF-β1 receptor expression was significantly lower compared with that of healthy controls. Attenuated TGF-β1 responsiveness mirrored by lower phospho-Smad2/3 expression after TGF-β1 stimulation and higher expression of inhibitory Smad7 was observed in monocytes from AD patients. During DC generation, mRNA expression of Smad7 was relatively higher in LC-like DCs of AD patients. Lower TNF-α expression of monocytes from AD patients might further contribute to attenuated TGF-β signaling in the disease since TNF-α had synergistic effects on TGF-β1 signaling and LC generation through mediating the degradation of Smad7. Our results demonstrate alleviated TGF-β1 signaling together with the amount of soluble co-factors might direct the nature of differentiating DCs.Keywords: Atopic dermatitis r Dendritic cells r Monocytes r TNF-α r TGF-β IntroductionAtopic dermatitis (AD) is one of the most common allergic inflammatory skin diseases affecting up to 20% of children and up to 3% of adults in the western society [1]. It has been shown that the interaction of inherited as well as environmental factors plays an important role in the pathogenesis of AD [1,2].Transforming growth factor beta1 (TGF-β1) is a multifunctional cytokine and TGF-β1 signaling is essential for the maintenance of immune tolerance [3]. Briefly, TGF-β1 signaling is initiated by binding of TGF-β1 to its heterodimeric transmembrane receptor complex, which is composed of type I (TGFβRI) and Correspondence: Prof. Natalija Novak e-mail: Natalija.Novak@ukb.uni-bonn.de type II (TGFβRII) receptors [4]. Binding of TGF-β1 results in the phosphorylation and activation of TGFβRI, which then activates TGFβRII [4]. The activated TGF-β receptors induce phosphorylation of Smad2 and Smad3 [5,6], which form a complex together with Smad4. The complex translocates into the nucleus and starts gene transcription and regulation [5][6][7][8]. The type III (TGFβRIII) receptor does not have signaling function but helps TGF-β to bind its receptors. Importantly, TGF-β1 signaling is suppressed by the expression of inhibitory Smad molecules, namely Smad7, which mediates degradation of TGFβRI and suppresses the phosphorylation of Smad2/Smad3 [9,10]. Several lines of evidence demonstrated that TGF-β1 exerts strong suppressive functions on epidermal and mucosal inflammation [11,12]. Animals with impaired TGF-β1 signaling develop...

TGF-β Activation and Function in Immunity

“…TGF-β-mediated differentiation of Langerhans cells appears to involve Axl, a receptor tyrosine kinase that is induced by TGF-β during Langerhans cell development (130). Langerhans cells isolated from patients with atopic dermatitis display reduced TGF-β signaling and TGF-β receptor expression, suggesting potential functional importance of TGF-β signaling in Langerhans cells in this disease (131). …”

Neutrophil Phagocytosis of Platelets in the Early Phase of 2,4,6-trinitro-1-chlorobenzene (TNCB)-induced Dermatitis in Mice

“…3). MPO is reported to be rapidly released by activated polymorphonuclear neutrophils, and it is decreased or absent when neutrophils phagocytize acti­vated platelets [6, 8], although some additional factors, such as transforming growth factor β signaling, may partially influence the MPO expression in neutrophils [10, 14, 18]. Platelet phagocytosis by activated neutrophils could be regarded as clearance of aggregated platelets in the vessels and may act in an inflammation-suppressing manner in inflamed dermis.…”

Pathogenesis of atopic dermatitis

“…(LNs) . Therefore, attenuated IFN‐γ and TGF‐β signalling and responsiveness of human monocytes from AD patients might promote Th2 immune responses due to decreased TGF‐β signalling on one hand and impaired Th1 cytokine IFN‐γ stimulation on the other hand.…”