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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    Immunity 04/2014; 40(4). DOI:10.1016/j.immuni.2014.01.014 · 21.56 Impact Factor
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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. To investigate the role of bronchial fibroblasts obtained from asthmatic subjects and healthy controls in regulating Th17 response by creating a local micro-environment that promotes this response in the airways. Human bronchial fibroblasts and CD4(+)T cells were isolated from atopic asthmatics and non-atopic healthy controls. CD4(+)T were co-cultured with bronchial fibroblasts of asthmatic subjects and healthy controls. RORc gene expression was detected by qPCR. Phosphorylated STAT-3 and RORγt were evaluated by western blots. Th17 phenotype was measured by flow cytometry. IL-22, IL17, IL-6 TGF-β and IL1-β were assessed by qPCR and ELISA. Co-culture of CD4(+)T cells with bronchial fibroblasts significantly stimulated RORc expression and induced a significant increase in Th17 cells as characterized by the percentage of IL-17(+)/CCR6(+) staining in asthmatic conditions. IL-17 and IL-22 were increased in both normal and asthmatic conditions with a significantly higher amount in asthmatics compared to controls. IL-6, IL-1β, TGF-β and IL-23 were significantly elevated in fibroblasts from asthmatic subjects upon co-culture with CD4(+)T cells. IL-23 stimulates IL-6 and IL-1β expression by bronchial fibroblasts. Interaction between bronchial fibroblasts and T cells seems to promote specifically Th17 cells profile in asthma. These results suggest that cellular interaction particularly between T cells and fibroblasts may play a pivotal role in the regulation of the inflammatory response in asthma.
    PLoS ONE 12/2013; 8(12):e81983. DOI:10.1371/journal.pone.0081983 · 3.23 Impact Factor
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    • "However, IL-1β and IL-23 are likely produced by other cells and may further support development of Th17 as seen in other studies of both H. pylori infection and cancer [43], [44]. Moreover, we did not exclude that GMFs can indirectly contribute to the IL-1β and IL-23 dependent Th17 upregulation in the gastric mucosa since human skin derived fibroblasts were demonstrated to support the expansion of Th17 cells via upregulation of the IL-23 production by dendritic cells via a process involving IL-1β [23]. Since DCs are important in Th17 development, the role of these cells in H. pylori infection and gastric cancer should be further examined. "
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    ABSTRACT: Gastric cancer is associated with chronic inflammation and Helicobacter pylori infection. Th17 cells are CD4(+) T cells associated with infections and inflammation; but their role and mechanism of induction during carcinogenesis is not understood. Gastric myofibroblasts/fibroblasts (GMF) are abundant class II MHC expressing cells that act as novel antigen presenting cells. Here we have demonstrated the accumulation of Th17 in H. pylori-infected human tissues and in the gastric tumor microenvironment. GMF isolated from human gastric cancer and H. pylori infected tissues co-cultured with CD4(+) T cells induced substantially higher levels of Th17 than GMF from normal tissues in an IL-6, TGF-β, and IL-21 dependent manner. Th17 required interaction with class II MHC on GMF for activation and proliferation. These studies suggest that Th17 are induced during both H. pylori infection and gastric cancer in the inflammatory milieu of gastric stroma and may be an important link between inflammation and carcinogenesis.
    PLoS ONE 01/2013; 8(1):e53798. DOI:10.1371/journal.pone.0053798 · 3.23 Impact Factor
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