Asunto(s)
Anticuerpos Monoclonales , Dermatitis Atópica , Progresión de la Enfermedad , Receptores de Interleucina-17 , Animales , Humanos , Ratones , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacología , Dermatitis Atópica/inmunología , Dermatitis Atópica/tratamiento farmacológico , Modelos Animales de Enfermedad , Receptores de Interleucina-17/inmunología , Receptores de Interleucina-17/antagonistas & inhibidoresRESUMEN
Natural killer (NK) cell is an essential cytotoxic lymphocyte in our innate immunity. Activation of NK cells is of paramount importance in defending against pathogens, suppressing autoantibody production and regulating other immune cells. Common gamma chain (γc) cytokines, including IL-2, IL-15, and IL-21, are defined as essential regulators for NK cell homeostasis and development. However, it is inconclusive whether γc cytokine-driven NK cell activation plays a protective or pathogenic role in the development of autoimmunity. In this study, we investigate and correlate the differential effects of γc cytokines in NK cell expansion and activation. IL-2 and IL-15 are mainly responsible for NK cell activation, while IL-21 preferentially stimulates NK cell proliferation. Blockade of Janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway by either JAK inhibitors or antibodies targeting γc receptor subunits reverses the γc cytokine-induced NK cell activation, leading to suppression of its autoimmunity-like phenotype in vitro. These results underline the mechanisms of how γc cytokines trigger autoimmune phenotype in NK cells as a potential target to autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes , Interleucina-2 , Humanos , Interleucina-2/metabolismo , Interleucina-15 , Citocinas/metabolismo , Quinasas Janus/metabolismo , Células Asesinas Naturales , Enfermedades Autoinmunes/tratamiento farmacológico , Janus Quinasa 3RESUMEN
Interleukins 4 (IL-4) and 21 (IL-21) belong to the common gamma chain cytokine family which are highly involved in the progression of autoimmune diseases. While IL-4 is well known to be involved in the suppression of apoptosis of autoreactive B cells, the role played by IL-21 remains unclear. In the current study, we activated the human Burkitt's lymphoma Ramos B cells with anti-IgM to mimic B cell hyperactivation observed in patients of autoimmune diseases. Consistent with other reported findings, anti-IgM led to the downregulation of proteins involved in B cell survival and proliferation, as well as the activation of caspase 3 activity and DNA damage, resulting in apoptotic cell death after 48-hour treatment. Although both IL-4 and IL-21 reversed anti-IgM-induced apoptosis and cell cycle arrest, they did so via different mechanisms: while IL-4 could directly suppress anti-IgM-induced caspase 3 activation and marker indicative of DNA damage, IL-21 could induce B cell proliferation in the presence of anti-IgM. Importantly, IL-21 also suppressed activation induced cell death in human primary B cells. Pre-treatment with clinically validated JAK inhibitors completely reversed the effects of IL-4 and IL-21 to rescue anti-IgM induced cell death and DNA damage. The results indicate the underlying mechanisms of how IL-4 and IL-21 differentially promote survival of hyperactivated B cells and provide hints to treat autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes , Linfoma de Células B , Anticuerpos Antiidiotipos , Apoptosis , Enfermedades Autoinmunes/tratamiento farmacológico , Caspasa 3/metabolismo , Humanos , Inmunoglobulina M , Interleucina-4/farmacología , Interleucinas/farmacologíaRESUMEN
SUMMARY: The interaction between tumor and immune system plays a crucial role in both cancer development and treatment response. To facilitate comprehensive investigation of tumor-immune interactions, we have designed a user-friendly web portal TISIDB, which integrated multiple types of data resources in oncoimmunology. First, we manually curated 4176 records from 2530 publications, which reported 988 genes related to anti-tumor immunity. Second, genes associated with the resistance or sensitivity of tumor cells to T cell-mediated killing and immunotherapy were identified by analyzing high-throughput screening and genomic profiling data. Third, associations between any gene and immune features, such as lymphocytes, immunomodulators and chemokines, were pre-calculated for 30 TCGA cancer types. In TISIDB, biologists can cross-check a gene of interest about its role in tumor-immune interactions through literature mining and high-throughput data analysis, and generate testable hypotheses and high quality figures for publication. AVAILABILITY AND IMPLEMENTATION: http://cis.hku.hk/TISIDB. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.