Data shown are from one human donor, representative of two donors. RvD1 enhances the expression of Bcl-6 in main human B Rabbit Polyclonal to CCR5 (phospho-Ser349) cells and in malignant B cell lymphoma We next investigated how RvD1 could reduce STAT6 binding affinity to the GLT promoter region without affecting the transcription of other IL4-inducible genes such as IL-4R and CD23. for IgE-driven diseases such as asthma and allergy. strong class=”kwd-title” Keywords: pro-resolving mediator, inflammation resolution, human, B cell, IgE Introduction Acute inflammation is a protective response brought on by trauma, pathogens, toxins, and other tissue insults, which is initiated within minutes of acknowledgement of danger signals by activation of the innate immune system. Resolution of inflammation is a dynamic and active process that regulates many cellular interactions in affected tissues to restore homeostasis [1C3]. Failure to re-establish homeostasis due to insufficient resolution can contribute to chronic inflammatory conditions, such as asthma [2, 3]. Recently, endogenous specialized pro-resolving lipid mediators (SPMs) were identified as important drivers of resolution of inflammation [3C6]. SPMs are derived from dietary polyunsaturated fatty acids, such as omega-3 and omega-6, and are classified into four families: lipoxins (LXs), resolvins (RvDs, RvEs), protectins (PDs) and maresins (MaRs) [7]. Many intermediates are involved in their biosynthetic pathway, such as 17-HDHA, which is a precursor of RvDs [1, 6]. Each lipid mediator has a unique chemical structure, which determines their specific bioaction on immune cells [8]. Recently, our lab has shown that this SPMs, 17-HDHA and RvD1, directly regulate human B-cell functions by promoting plasma cell differentiation and increasing IgM and IgG antibody production, and these may serve as a new class of adjuvants [9]. However, an important issue is whether or not SPMs affect human B-cell IgE antibody production. IgE SJFα is an antibody produced by B cells that is responsible for the onset and maintenance of allergic diseases, including asthma [10, 11]. The vast majority of individuals with allergic asthma have elevated serum IgE levels, which is a reliable parameter that tracts with uncontrolled and severe asthma [12]. IgE is produced from B cells stimulated by cytokines and co-stimulatory signals from Th2 cells, in response to specific allergens. SJFα Antigen cross-linking of IgE bound to Fc receptors on mast cells or basophils triggers cascades of pro-inflammatory immune reactions presumably to obvious pathogens such as parasites [13]. However, when this process is not terminated acutely or with repeated exposure to allergens, it can lead to chronic inflammation, causing tissue damage. Because IgE is usually a key player in allergic diseases, control of IgE levels, such as via anti-IgE antibodies, has emerged as an important therapeutic strategy [10, 11]. Given the important role of SPMs in promoting inflammation resolution, some studies have investigated the functions of SPMs in murine models of inflammation, including asthma [14C16]. Resolvin D1 (RvD1) reduces allergic airway inflammation by targeting eosinophils and pro-inflammatory mediators involved in Th2 signaling pathway, while resolvin E1 (RvE1) regulates the development of Th17 cells and IL-23 production [14, 15]. However, there is an important knowledge gap regarding the effects of SPMs on human B-cell IgE production, which has a central role in initiating allergic diseases. In this study, we asked whether SPMs can regulate human B-cell IgE production. We demonstrate that RvD1 and 17-HDHA specifically suppress IgE production in human B cells by inhibiting B-cell class switch to IgE. This is mediated by Bcl-6 (B cell lymphoma-6), the transcriptional repressor, which is known to control SJFα IgE production by competing with STAT6 (transmission transducer and activator of transcription 6) for binding to the promoter region of epsilon germline transcript (GLT). The important regulatory role of Bcl-6 was also shown in Bcl-6 knockout mice which exhibited extremely high serum IgE levels [17]. Therefore, these pro-resolving lipid mediators may represent a novel treatment pathway for allergic diseases with their unique actions on regulating human B-cell IgE production. Results 17-HDHA and RvD1 decrease IgE production from human B cells Several different IgE inducing cocktails have been reported, however, some modifiers such as IL-21 and CpG ODNs are reported to have different effects by different groups [18C22]. To investigate the effect of SPMs on IgE production, we first decided the optimal conditions for.
