RESUMEN
Human interleukin-22 (IL-22), a cytokine with structural homology to IL-10, is produced by activated T cells. The IL-22 receptor complex consists of a ligand-binding chain, the IL-22R1 and a signal-transducing chain, the IL-10R2. The aim of this study is to identify potential target cells and associated biological activity of IL-22 by identifying cell types that specifically express high levels of IL-22R1 as the expression of IL-10R2 is ubiquitous. Expression of IL-22R1 mRNA, as analyzed by real time quantitative polymerase chain reaction (PCR), was observed in human tumor cell lines of stromal or epithelial origin derived from liver, pancreas, colon and lung tissue. Furthermore, we examined the ability of IL-22 to activate the JAK-Signal Transducer and Activator of Transcription (STAT) pathway in epithelial cells of the colon. IL-22 induced the phosphorylation of STAT1 and STAT3 in Colo205, a colon epithelial cell line. Consequently, IL-22 upregulated mRNA for Suppressor of Cytokine Signaling 3 (SOCS3), a STAT3-responsive gene. Further analyses, by real time quantitative PCR, on a panel of chemokines and immune function related genes revealed that IL-22 induced expression of the acute phase proteins alpha-Antichymotrypsin and Serum Amyloid A, as well as IL-10 mRNA and protein production by Colo205. Induction of IL-10 by IL-22, in Colo205 cells, could be inhibited in the presence of a neutralizing antibody against IL-10R2. IL-22-mediated effects on the Colo205 cells were also inhibited in the presence of IL-22 binding protein (IL-22BP), a soluble receptor with structural similarity to IL-22R1. The high levels of expression of IL-22R1 observed in epithelial cells of the colon and the ability of IL-22 to upregulate production of acute phase proteins and IL-10 in Colo205 cells, suggest a functional role for IL-22 in intestinal inflammation.
Asunto(s)
Colon/metabolismo , Colon/patología , Proteínas de Unión al ADN/metabolismo , Interleucina-10/metabolismo , Interleucinas/metabolismo , Transactivadores/metabolismo , Animales , Colon/efectos de los fármacos , Proteínas de Unión al ADN/efectos de los fármacos , Proteínas de Unión al ADN/genética , Células Epiteliales/química , Humanos , Interleucina-10/antagonistas & inhibidores , Interleucinas/farmacología , Ratones , Fosforilación/efectos de los fármacos , ARN Mensajero , Receptores de Interleucina/efectos de los fármacos , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Factor de Transcripción STAT1 , Factor de Transcripción STAT3 , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Transactivadores/efectos de los fármacos , Transactivadores/genética , Células Tumorales Cultivadas , Regulación hacia Arriba , Interleucina-22RESUMEN
Whether epithelial cells play a role in triggering the immune cascade leading to T helper 2 (T(H)2)-type allergic inflammation is not known. We show here that human thymic stromal lymphopoietin (TSLP) potently activated CD11c(+) dendritic cells (DCs) and induced production of the T(H)2-attracting chemokines TARC (thymus and activation-regulated chemokine; also known as CCL17) and MDC (macrophage-derived chemokine; CCL22). TSLP-activated DCs primed naïve T(H) cells to produce the proallergic cytokines interleukin 4 (IL-4), IL-5, IL-13 and tumor necrosis factor-alpha, while down-regulating IL-10 and interferon-gamma. TSLP was highly expressed by epithelial cells, especially keratinocytes from patients with atopic dermatitis. TSLP expression was associated with Langerhans cell migration and activation in situ. These findings shed new light on the function of human TSLP and the role played by epithelial cells and DCs in initiating allergic inflammation.
Asunto(s)
Antígenos CD11 , Citocinas/inmunología , Células Dendríticas/inmunología , Dermatitis Atópica/inmunología , Interleucina-7/inmunología , Células Th2/inmunología , Timo/inmunología , Adulto , Biomarcadores , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , División Celular , Células Cultivadas , Técnicas de Cocultivo , Citocinas/genética , Citocinas/farmacología , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Dermatitis Atópica/patología , Células Epiteliales/citología , Células Epiteliales/inmunología , Expresión Génica , Humanos , Interleucina-7/farmacología , Células de Langerhans/citología , Células de Langerhans/inmunología , Tonsila Palatina/inmunología , ARN Mensajero , Piel/inmunología , Piel/patología , Células Th2/citología , Linfopoyetina del Estroma TímicoRESUMEN
We have biologically characterized two new members of the IL-17 cytokine family: IL-17F and IL-25. In contrast to conventional in vitro screening approaches, we have characterized the activity of these new molecules by direct in vivo analysis and have compared their function to that of other IL-17 family members. Intranasal administration of adenovirus expressing IL-17, IL-17C, or IL-17F resulted in bronchoalveolar lavage neutrophilia and inflammatory gene expression in the lung. In contrast, intranasal administration of IL-25-expressing adenovirus or IL-25 protein resulted in the production of IL-4, IL-5, IL-13, and eotaxin mRNA in the lung and marked eosinophilia in the bronchoalveolar lavage and lung tissue. Mice given intranasal IL-25 also developed epithelial cell hyperplasia, increased mucus secretion, and airway hyperreactivity. IL-25 gene expression was detected following Aspergillus and Nippostrongylus infection in the lung and gut, respectively. IL-25-induced eosinophilia required IL-5 and IL-13, but not IL-4 or T cells. Following IL-25 administration, the IL-5(+) staining cells were CD45R/B220(+), Thy-1(+/-), but were NK1.1-, Ly-6G(GR-1)-, CD4-, CD3-, and c-kit-negative. gamma-common knockout mice did not develop eosinophilia in response to IL-25, nor were IL-5(+) cells detected. These findings suggest the existence of a previously unrecognized cell population that may initiate Th2-like responses by responding to IL-25 in vivo. Further, these data demonstrate the heterogeneity of function within the IL-17 cytokine family and suggest that IL-25 may be an important mediator of allergic disease via production of IL-4, IL-5, IL-13, and eotaxin.