RESUMO
Basophils are important effector cells in allergic disorders and anti-parasitic immune response. A number of activators including interleukin 3 (IL-3) and IgE have been identified in the regulation of human basophils expressing mediators such as histamine and leukotriene C4 (LTC4) and cytokines, including IL-4 and IL-13. Human basophils express high levels of IL-2 receptors. However, the function of the IL-2 pathway in basophils remains unknown. Here, we identified that IL-2 induced the activation of human basophils in vitro to express a variety of inflammatory cytokines and chemokines including IL-5, IL-13, GM-CSF and CCL-17. This effect by IL-2 is confirmed by an upstream regulator analysis using Ingenuity pathway analysis. Of note, one of the top regulated cytokines, IL-5, was for the first time identified to be induced by IL-2 in human basophils rather than IL-3 or anti-IgE. Immunofluorescence analysis of skin specimens from bullous pemphigoid and eczema revealed that infiltrating basophils in skin lesions widely expressed IL-5 and GM-CSF. Together, our findings reveal IL-2 as a novel regulator of human basophils. This adds a new layer to support the importance of basophils in allergic disorders.
Assuntos
Basófilos/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-2/farmacologia , Interleucina-5/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Basófilos/imunologia , Basófilos/metabolismo , Células Cultivadas , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Eczema/genética , Eczema/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Interleucina-5/metabolismo , Penfigoide Bolhoso/genética , Penfigoide Bolhoso/metabolismo , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologiaRESUMO
Schistosomiasis is a chronic disease caused by the parasite of the Schistosoma genus and is characterized by egg-induced hepatic granulomas and fibrosis. Macrophages play a central role in schistosomiasis with several studies highlighting their differentiation into M2 cells involved in the survival of infected mice through limitation of immunopathology. However, little is known regarding the mechanisms of regulating macrophage differentiation. Here, we showed that the early stage of infection by Schistosoma japonicum induced expression of type 1T-helper-cell (Th1) cytokine, interferon-γ (IFN-γ), leading to increase in M1 cells. However, the presence of liver-trapped eggs induced the expression of Th2 cytokines including interleukin-4 (IL-4), IL-10, and IL-13 that upregulated the transcription of miR-146b by activating signal transducer and activator of transcription 3/6 (STAT3/6) that bind to the promoter of the pre-miR-146b gene. We found that the miR-146a/b was significantly upregulated in macrophages during the progression of hepatic schistosomiasis. The elevated miR-146a/b inhibited the IFN-γ-induced differentiation of macrophages to M1 cells through targeting STAT1. Our data indicate the protective roles of miR-146a/b in hepatic schistosomiasis through regulating the differentiation of macrophages into M2 cells.
Assuntos
Hepatopatias Parasitárias/genética , Macrófagos/metabolismo , MicroRNAs/genética , Interferência de RNA , Fator de Transcrição STAT1/genética , Esquistossomose/genética , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica , Hepatopatias Parasitárias/parasitologia , Hepatopatias Parasitárias/patologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Masculino , Camundongos , Modelos Biológicos , Esquistossomose/parasitologia , Esquistossomose/patologia , Células Th2/imunologia , Células Th2/metabolismoRESUMO
OBJECTIVE: To investigate the effect of sonic hedgehog (SHH) on the proliferation of synovial fibroblasts (SFs). METHODS: The serum samples were collected from 30 rheumatoid arthritis (RA) patients, 30 systemic lupus erythematosus (SLE) patients, 30 ankylosing spondylitis (AS) patients and 30 healthy subjects. The concentrations of serum SHH were detected by ELISA. Collagen induced arthritis (CIA) were developed by type 2 collagen in Sprague-Dawley rats. The SFs were isolated from knee synovial tissues of CIA rats, and then identified by the detection of vimentin by immunofluorescence technique. Before and 72 hours after blocking SHH-glioma-associated oncogene 1 (Gli-1) signaling pathway with GANT61, the expression level of SHH in SFs was detected by Western blotting, and the proliferation of SFs was examined with CCK-8 assay. RESULTS: The level of serum SHH in the RA patients was remarkably higher than that in the SLE, AS patients and the healthy controls. In the CIA rats, the expression of SHH in SFs in vitro was higher than that in the healthy control rats. After 72-hour treatment of GANT61 to block SHH-Gli-1 signaling pathway, the expression level of SHH protein in SFs from CIA rats was reduced, and meanwhile the proliferation of the SFs was inhibited. CONCLUSION: SHH plays an important role in the proliferation of SFs and could be used as a potential therapeutic target for RA.
