Inflammatory signal induced IL-10 production of marginal zone B-cells depends on CREB

• Published in: Immunology letters 2019-08, Vol.212, p.14-21
• Main Authors: Barátki, Balázs L., Huber, Krisztina, Sármay, Gabriella, Matkó, János, Kövesdi, Dorottya
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - metabolism; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cells, Cultured; CREB; Cyclic AMP Response Element-Binding Protein - immunology; Cyclic AMP Response Element-Binding Protein - metabolism; Gene Expression Regulation - immunology; IL-10; Inflammation; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin-10 - genetics; Interleukin-10 - immunology; Lymph Nodes - cytology; Lymph Nodes - immunology; Marginal zone B-cells; Mice; Mice, Inbred DBA; Phosphorylation - immunology; Primary Cell Culture; Receptors, Antigen, B-Cell - immunology; Receptors, Antigen, B-Cell - metabolism; Signal Transduction - genetics; Signal Transduction - immunology; Spleen - cytology; Spleen - immunology; Toll-Like Receptor 9 - immunology; Toll-Like Receptor 9 - metabolism
• ISSN: 0165-2478; 1879-0542
• DOI: 10.1016/j.imlet.2019.06.004

•The BCR, TLR9 and IFN-γ receptors induce IL-10 expression by MZ B-cells.•Activation of CREB is prolonged in MZ B-cells but not in FO B-cells.•Sustained phosphorylation of CREB is associated with its prolonged binding to CBP.•Inhibition of CREB binding to CBP decreases IL-10 production by MZ B-cells.•Prolonged CREB activation needed for IL-10 production by B-cells during inflammation. IL-10 is a suppressive cytokine that has been implicated in the pathophysiology of autoimmune disorders and can be produced by different cell types such as regulatory B-cells. Our previous work showed that under inflammatory condition MZ B-cells differentiated into IL-10 producing cells and contributed to the downregulation of collagen-induced arthritis, while follicular B-cells failed to do so. Based on these observations, we aimed to investigate how inflammatory signals mediated through the BCR, TLR9 and IFN-γ receptors trigger IL-10 production in MZ B-cells but leave FO B-cells unresponsive. We particularly focused on the CREB transcription factor as it is involved in all three signalling cascades and analysed its contribution to IL-10 production. Our results demonstrate that the IL-10 production of MZ B-cells induced by the BCR, TLR9 and IFN-γ receptors is mediated by CREB. We showed that the activation of CREB is prolonged in MZ B-cells while the transcription factor only transiently phosphorylated in FO B-cells. The sustained phosphorylation of CREB is clearly associated with its prolonged binding to molecular partner CBP, whereas inhibition of their association decreased IL-10 production. We assume that sustained activation of CREB is required for IL-10 production by B-cells under inflammatory conditions.