Schirmer C, Klein C, von Bergen M et al.Human fibroblasts support the expansion of IL-17-producing T cells via up-regulation of IL-23 production by dendritic cells. Blood 116:1715-25

Department of Dermatology, Venerology and Allergology, Medical Faculty of the Leipzig University, Leipzig, Germany.
Blood (Impact Factor: 10.45). 09/2010; 116(10):1715-25. DOI: 10.1182/blood-2010-01-263509
Source: PubMed


The initiation of immune responses is associated with the maturation of dendritic cells (DCs) and their migration to draining lymph nodes. En route activated DCs encounter cells of the tissue microenvironment, such as fibroblasts. Because we have shown that DCs interact with fibroblasts during immune responses, we studied the impact of skin fibroblasts on human monocyte-derived DC function and subsequent human T-cell (TC) differentiation. We show that fibroblasts support interleukin-23 (IL-23) secretion from DCs preactivated by lipopolysaccharide (DC(act)) compared with lipopolysaccharide-activated DCs alone. The underlying complex feedback-loop mechanism involves IL-1β/tumor necrosis factor-α (from DC(act)), which stimulate fibroblasts prostaglandin E(2) production. Prostaglandin E(2), in turn, acts on DC(act) and increases their IL-23 release. Furthermore, fibroblast-stimulated DC(act) are far superior to DC(act) alone, in promoting the expansion of Th17 cells in a Cox-2-, IL-23-dependent manner. Using CD4(+)CD45RO(+) memory TCs and CD4(+)CD45RA(+) naive TCs, we showed that fibroblasts induce a phenotype of DC(act) that promotes the expansion of Th17 cells. Moreover, in psoriasis, a prototypic immune response in which the importance of IL-23/Th17 is known, high expression of Cox-2 in fibroblasts was observed. In conclusion, skin fibroblasts are involved in regulation of IL-23 production in DCs and, as a result, of Th17 expansion.

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    • "The skin possesses inhibitory cytokines, vitamins, and lipid mediators (Biggs et al., 2010; Schirmer et al., 2010). For instance, vitamin D 3 and IL-10 play regulatory roles in skin inflammation (Biggs et al., 2010). "
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    ABSTRACT: Mast cells (MCs) mature locally, thus possessing tissue-dependent phenotypes for their critical roles in both protective immunity against pathogens and the development of allergy or inflammation. We previously reported that MCs highly express P2X7, a receptor for extracellular ATP, in the colon but not in the skin. The ATP-P2X7 pathway induces MC activation and consequently exacerbates the inflammation. Here, we identified the mechanisms by which P2X7 expression on MCs is reduced by fibroblasts in the skin, but not in the other tissues. The retinoic-acid-degrading enzyme Cyp26b1 is highly expressed in skin fibroblasts, and its inhibition resulted in the upregulation of P2X7 on MCs. We also noted the increased expression of P2X7 on skin MCs and consequent P2X7- and MC-dependent dermatitis (so-called retinoid dermatitis) in the presence of excessive amounts of retinoic acid. These results demonstrate a unique skin-barrier homeostatic network operating through Cyp26b1-mediated inhibition of ATP-dependent MC activation by fibroblasts.
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    • "Thus, in arthritis, synovial macrophages support Th17 cell differentiation via a network of cytokines [14]. In skin, fibroblasts support the expansion of Th17 via IL-23 [15]. Moreover, fibroblasts can release cytokines that are involved in Th17 differentiation such as IL-6 and TGF-β [16,17]. "
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    ABSTRACT: Airway inflammation is an important characteristic of asthma and has been associated with airway remodelling and bronchial hyperreactivity. The mucosal microenvironment composed of structural cells and highly specialised extracellular matrix is able to amplify and promote inflammation. This microenvironment leads to the development and maintenance of a specific adaptive response characterized by Th2 and Th17. Bronchial fibroblasts produce multiple mediators that may play a role in maintaining and amplifying this response in asthma.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "Further studies are needed to verify the effects of Ni on the IL-6 production. Dermal fibroblasts regulate DCs function by producing inflammatory cytokines and prostanoids (Saalbach et al., 2010;Schirmer et al., 2010), indicating that dermal fibroblasts are one of the important players in the pathogenesis of skin inflammation . Because Ni is challenged intradermally to ear pinnas, it can directly stimulate the dermal fibroblasts in our mouse model (Sato et al., 2007). "
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    ABSTRACT: Nickel (Ni) has been shown to be one of the most frequent metal allergens. We have already reported a murine metal allergy model with pathogen-associated molecular patterns (PAMPs) as adjuvants. Interleukin (IL)-1β plays a critical role in our mouse model. Because nonimmune cells, including fibroblasts, play important roles in local allergic inflammation, we investigated whether Ni induced inflammatory responses in mouse dermal fibroblasts (MDF). We also analyzed the synergistic effects between Ni, PAMPs, and IL-1β. MDF stimulated with Ni produced a significantly higher amount of nitric oxide (NO) in a dose-dependent manner. NO production was augmented by costimulation with IL-1β, but not with PAMPs. On the other hand, IL-1β or PAMPs induced a significantly higher amount of IL-6 production by MDF, but no augmentation was detected in the presence of Ni. A specific inhibitor for inducible nitric oxide synthase (iNOS) inhibited Ni-induced NO production. iNOS mRNA expression was significantly higher in MDF stimulated with Ni, IL-1β, or both. A specific inhibitor for hypoxia inducible factor (HIF)-2α, but not HIF-1α, inhibited NO production. Another frequent metal allergen, cobalt, also induced iNOS expression and NO production by MDF via the HIF-2α dependent pathway. The inhibitor for iNOS augments augmented ear swelling in Ni allergy mouse model. On the other hand, HIF-2α inhibitor attenuates allergic inflammation. These results indicate that metal allergens induce NO production in MDF via the HIF-2α dependent pathway and IL-1β augments NO production, which suggests that the NO induced by metal allergens plays a pathological role in metal allergies.
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