Neuropeptide Calcitonin Gene-Related Peptide Promotes Immune Homeostasis of Bacterial Meningitis by Inducing Major Histocompatibility Complex Class II Ubiquitination.

BACKGROUND: Calcitonin gene-related peptide (CGRP), an immunomodulatory neuropeptide, is important for regulating pain transmission, vasodilation, and the inflammatory response. However, the molecular mechanisms of the CGRP-mediated immune response remain unknown. METHODS: The effects of CGRP on bacterial meningitis (BM) and its underlying mechanisms were investigated in BM mice in vivo and macrophages in vitro. RESULTS: Peripheral injection of CGRP attenuated cytokine storms and protected mice from fatal pneumococcal meningitis, marked by increased bacterial clearance, improved neuroethology, and reduced mortality. When the underlying mechanisms were investigated, we found that CGRP induces proteasome-dependent degradation of major histocompatibility complex class II (MHC-II) in macrophages and then inhibits CD4+ T-cell activation. MARCH1 was identified as an E3 ligase that can be induced by CGRP engagement and promote K48-linked ubiquitination and degradation of MHC-II in macrophages. These results provide new insights into neuropeptide CGRP-mediated immune regulation mechanisms. CONCLUSIONS: We conclude that targeting the nervous system and manipulating neuroimmune communication is a promising strategy for treating intracranial infections like BM.

Sleep deprivation reduced LPS-induced IgG2b production by up-regulating BMAL1 and CLOCK expression.

Sleep deprivation (SD) weakens the immune system and leads to increased susceptibility to infectious or inflammatory diseases. However, it is still unclear how SD affects humoral immunity. In the present study, sleep disturbance was conducted using an sleep deprivation instrument, and the bacterial endotoxin lipopolysaccharide (LPS) was used to activate the immune response. It was found that SD-pretreatment reduced LPS-induced IgG2b+ B cells and IgG2b isotype antibody production in lymphocytes of spleen. And, SD-pretreatment decreased the proportion of CD4+T cells, production of CD4+T cells derived TGF-ß1 and its contribution in helping IgG2b production. Additionally, BMAL1 and CLOCK were selectively up-regulated in lymphocytes after SD. Importantly, BMAL1 and CLOCK deficiency contributed to TGF-ß1 expression and production of IgG2b+ B cells. Thus, our results provide a novel insight to explain the involvement of BMAL1 and CLOCK under SD stress condition, and their roles in inhibiting TGF-ß1 expression and contributing to reduction of LPS induced IgG2b production.

Human C15orf39 Inhibits Inflammatory Response via PRMT2 in Human Microglial HMC3 Cell Line.

Microglia-mediated inflammatory response is one key cause of many central nervous system diseases, like Alzheimer's disease. We hypothesized that a novel C15orf39 (MAPK1 substrate) plays a critical role in the microglial inflammatory response. To confirm this hypothesis, we used lipopolysaccharide (LPS)-and interferon-gamma (IFN-γ)-induced human microglia HMC3 cells as a representative indicator of the microglial in vitro inflammatory response. We found that C15orf39 was down-regulated when interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) expression increased in LPS/IFN-γ-stimulated HMC3 cells. Once C15orf39 was overexpressed, IL-6 and TNFα expression were reduced in LPS/IFN-γ-stimulated HMC3 cells. In contrast, C15orf39 knockdown promoted IL-6 and TNFα expression in LPS/IFN-γ-stimulated HMC3 cells. These results suggest that C15orf39 is a suppressive factor in the microglial inflammatory response. Mechanistically, C15orf39 interacts with the cytoplasmic protein arginine methyltransferase 2 (PRMT2). Thus, we termed C15orf39 a PRMT2 interaction protein (PRMT2 IP). Furthermore, the interaction of C15orf39 and PRMT2 suppressed the activation of NF-κB signaling via the PRMT2-IκBα signaling axis, which then led to a reduction in transcription of the inflammatory factors IL6 and TNF-α. Under inflammatory conditions, NF-κBp65 was found to be activated and to suppress C15orf39 promoter activation, after which it canceled the suppressive effect of the C15orf39-PRMT2-IκBα signaling axis on IL-6 and TNFα transcriptional expression. In conclusion, our findings demonstrate that in a steady condition, the interaction of C15orf39 and PRMT2 stabilizes IκBα to inhibit IL-6 and TNFα expression by suppressing NF-κB signaling, which reversely suppresses C15orf39 transcription to enhance IL-6 and TNFα expression in the microglial inflammatory condition. Our study provides a clue as to the role of C15orf39 in microglia-mediated inflammation, suggesting the potential therapeutic efficacy of C15orf39 in some central nervous system diseases.

Mendelian randomization study on the causal effect of chickenpox on dementia.

Some viruses, such as varicella zoster virus, are associated with severe dementia. The present study aims to identify the causal link between chickenpox and dementia. To date, the largest publicly available genome-wide association study (GWAS) for chickenpox (710 cases and 211 856 controls from European individuals) and for dementia (5933 cases and 212 859 controls from European individuals) were used to performed this two-sample Mendelian randomization (MR) study. We found no significant pleiotropy or heterogeneity in all seven selected chickenpox genetic instrumental variants in dementia GWAS. Of seven chickenpox genetic variants, two are located in the intergenic region and five are located in intron. We found that as chickenpox genetically increased, dementia risk increased based on an inverse-variance weighted analysis (ß = 0.070, 95% confidence interval [CI] for ß: 0.014-0.126; odds ratio [OR] = 1.073, 95% CI for OR: 1.015-1.134; p = 0.014) and weighted median (ß = 0.071, 95% CI for ß: 0.002-0.141; OR = 1.074, 95% CI for OR: 1.002-1.152; p = 0.045). Reverse MR analysis showed no causal effect of dementia on chickenpox. Our analysis suggests a causal effect of genetically increased chickenpox on dementia risk. Thus, chickenpox may be a potential risk factor for dementia.

Chickenpox and multiple sclerosis: A Mendelian randomization study.

Observational studies have suggested a suspected association between varicella-zoster virus (VZV) infection and multiple sclerosis (MS), but the connection has remained unclear. The aim of the present study is to evaluate the causal relationship between chickenpox which is caused by VZV infection and MS. We performed a two-sample Mendelian randomization analysis to investigate the association of chickenpox with MS using summary statistics from genome-wide association studies (GWAS). The GWAS summary statistics data for chickenpox was from the 23andMe cohort including 107 769 cases and 15 982 controls. A large summary of statistical data from the International Multiple Sclerosis Genetics Consortium (IMSGC) was used as the outcome GWAS data set, including 14 802 MS cases and 26 703 controls. We found evidence of a significant association between genetically predicted chickenpox and risk of MS (odds ratio [OR] = 35.27, 95% confidence interval [CI] = 22.97-54.17, p = 1.46E-59). Our findings provided evidence indicating a causal effect of chickenpox on MS. Further elucidations of this association and underlying mechanisms are needed for identifying feasible interventions to promote MS prevention.

Negative Regulation of RIG-I by Tim-3 Promotes H1N1 Infection.

The mechanisms by which retinoic acid-inducible gene I (RIG-I), a critical RNA virus sensor, is regulated in many biological and pathological processes remain to be determined. Here, we demonstrate that T cell immunoglobulin and mucin protein-3 (Tim-3), an immune checkpoint inhibitor, mediates infection tolerance by suppressing RIG-I-type I interferon pathway. Overexpression or blockade of Tim-3 affects type I interferon expression, virus replication, and tissue damage in mice following H1N1 infection. Tim-3 signaling decreases RIG-I transcription via STAT1 in macrophages and promotes the proteasomal dependent degradation of RIG-I by enhancing K-48-linked ubiquitination via the E3 ligase RNF-122. Silencing RIG-I reversed Tim-3 blockage-mediated upregulation of type I interferon in macrophages. We thus identified a new mechanism through which Tim-3 mediates the immune evasion of H1N1, which may have clinical implications for the treatment of viral diseases.

Mendelian randomization study on causal association of IL-6 signaling with pulmonary arterial hypertension.

BACKGROUND: A recent Mendelian randomization (MR) did not support an effect of the lead interleukin-6 receptor (IL-6 R) variant on risk of pulmonary arterial hypertension (PAH). Thus, we used two sets of genetic instrumental variants (IVs) and publicly available PAH genome-wide association studies (GWAS) to reassess the genetic causal link between IL-6 signaling and PAH. METHODS: Six independent IL-6 signaling and 34 independent soluble IL-6 receptor (sIL-6 R) genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. RESULTS: We found that as IL-6 signaling genetically increased, the risk of PAH reduced using IVW (odds ratio [OR] = 0.023, 95% confidence interval [CI]: 0.0013-0.393; p = .0093) and weighted median (OR = 0.033, 95% CI: 0.0024-0.467; p = .0116). Otherwise, as sIL-6 R genetically increased, the risk of PAH increased using IVW (OR = 1.34, 95% CI: 1.16-1.56; p = .0001), weighted median (OR = 1.36, 95% CI: 1.10-1.68; p = .005), MR-Egger (OR = 1.43, 95% CI: 1.05-1.94; p = .03), and weighted mode (OR = 1.35, 95% CI for OR: 1.12-1.63; p = .0035). CONCLUSION: Our analysis suggested the causal link between genetically increased sIL-6 R and increased risk of PAH and between genetically increased IL-6 signaling and reduced risk of PAH. Thus, higher sIL-6 R levels may be a risk factor for patients with PAH, whereas higher IL-6 signaling may be a protective factor for patients with PAH.

The E3 ubiquitin ligase Itch deficiency promotes antigen-driven B-cell responses in mice.

Deficiency of Itch, an E3 ubiquitin ligase, usually induced severe systemic and progressive autoimmune disease. The Itch function is well studied in T cells but not in B cells. We hypothesize that B-cell-specific Itch deficiency promoted antigen-induced B-cell activation and antibody-expressing plasma cell (PC) production. We found that unlike Itch KO, Itch cKO (CD19cre Itchf/f ) mice did not demonstrated a significant increase in the sizes of spleens and LNs, antibody level, and base mutation of antibody gene. However, in line with the fact that Itch expression decreased in GC B cells, PCs, and plasmablast (PB)-like SP 2/0 cells, Itch deficiency promoted B-cell activation and antibody production induced by antigens including lipopolysaccharide (LPS) and sheep red blood cells (SRBCs). Mechanistically, we found that Itch deficiency promotes antigen-induced cytokine production because Itch controls the proteins (e.g., eIF3a, eIF3c, eIF3h) with translation initiation factor activity. Altogether, our data suggest that Itch deficiency promotes antigen-driven B-cell response. This may provide hints for Itch-targeted treatment of patients with autoimmune disease.

Mendelian randomization study updates the effect of 25-hydroxyvitamin D levels on the risk of multiple sclerosis.

BACKGROUND: Observational studies and previous Mendelian randomization (MR) studies have shown that genetically low 25-hydroxyvitamin D (25OHD) levels are associated with a high susceptibility to multiple sclerosis (MS). The present MR study aims to update the causal estimates for the effects of 25OHD levels on MS risk. METHODS: To date, the largest genome-wide association study (GWAS) for serum 25OHD (n = 401,460) and MS (14,498 MS cases and 24,091 controls) was used to assess the effect of serum 25OHD levels on MS. All participants were of European ancestry. The MR-egger_intercept test and Cochran's Q statistic were used to determine the pleiotropy and the heterogeneity, respectively. MR-egger, weighted median, inverse variance weighted (multiplicative random effects), simple mode, and weighted mode methods were used to evaluate the causal association of serum 25OHD levels with MS. Finally, the effect of a single 25OHD SNP (single nucleotide polymorphism) on MS was used to test the SNP bias. RESULTS: One hundred and fifteen newly identified serum 25OHD genetic variants were extracted from a large-scale serum 25OHD GWAS dataset. The 20 most effective and independent 25OHD genetic instrumental variables were extracted from the MS GWAS summary statistics. Pleiotropy analysis suggested no significant pleiotropic variant among the 20 selected 25OHD genetic instrument variants in MS GWAS datasets. As serum levels of 25OHD based on genetic changes increased, the risk of MS decreased using MR-egger (Beta = - 0.940, p = 0.001; OR = 0.391), weighted median (Beta = - 0.835, p = 0.000; OR = 0.434), IVW (Beta = - 0.781, p = 0.000; OR = 0.458), simple mode (Beta = - 1.484, p = 0.016; OR = 0.227), and weighted mode (Beta = - 0.913, p = 0.000; OR = 0.401). Our results were robust, with no obvious bias based on investigating the single 25OHD SNP on MS. CONCLUSIONS: Our analysis suggested a causal association between genetically increased serum 25OHD levels and reduced MS in the European population.

Mendelian randomization study on the causal effects of COVID-19 on childhood intelligence.

Although individuals with coronavirus disease 2019 (COVID-19) are known to be at increased risk for other conditions resulting from pathogenic changes (including metaplastic or anaplastic) in the lungs and other organs and organ systems, it is still unknown whether COVID-19 affects childhood intelligence. The present two-sample Mendelian randomization study aims to identify the genetic causal link between COVID-19 and childhood intelligence. Four COVID-19 genetic instrumental variants (IVs) were chosen from the largest genome-wide association studies (GWAS) for COVID-19 (hospitalized vs. population) (6406 cases and 902 088 controls of European ancestry). The largest childhood intelligence GWAS (n = 12 441 individuals of European ancestry) was used to evaluate the effect of the identified COVID-19-associated genetic IVs on childhood intelligence. We found that as the genetic susceptibility to COVID-19 increased, childhood intelligence followed a decreasing trend, according to mr_egger (ß = -0.156; p = 0.601; odds ratio [OR] = 0.856; 95% confidence interval [CI]: 0.522-1.405), simple mode (ß = -0.126; p = 0.240; OR = 0.882; 95% CI: 0.745-1.044), and weighted mode (ß = -0.121; p = 0.226; OR = 0.886; 95% CI: 0.758-1.036) analyses. This trend was further demonstrated by the weighted median (ß = -0.134; p = 0.031; OR = 0.875; 95% CI: 0.774-0.988) and the inverse variance weighted (ß = -0.152; p = 0.004; OR = 0.859; 95% CI: 0.776-0.952). Our analysis suggests a causal link between genetically increased COVID-19 and decreased childhood intelligence. Thus, COVID-19 may be a risk factor for declines in childhood intelligence.

Gm40600 promotes CD4+ T-cell responses by interacting with Ahnak.

It is important to characterize novel proteins involved in T- and B-cell responses. Our previous study demonstrated that a novel protein, Mus musculus Gm40600, reduced the proliferation of Mus musculus plasmablast (PB)-like SP 2/0 cells and B-cell responses induced in vitro by LPS. In the present study, we revealed that Gm40600 directly promoted CD4+ T-cell responses to indirectly up-regulate B-cell responses. Importantly, we found that CD4+ T-cell responses, including T-cell activation and differentiation and cytokine production, were increased in Gm40600 transgenic (Tg) mice and were reduced in Gm40600 knockout (KO) mice. Finally, we demonstrated that Gm40600 promoted the Ahnak-mediated calcium signalling pathway by interacting with Ahnak to maintain a cytoplasmic lateral location of Ahnak in CD4+ T cells. Collectively, our data suggest that Gm40600 promotes CD4+ T-cell activation to up-regulate the B-cell response via interacting with Ahnak to promote the calcium signalling pathway. The results suggest that targeting Gm40600 may be a means to control CD4+ T-cell-related diseases.

T cell immunoglobulin and mucin domain protein 3 inhibits glycolysis in RAW 264.7 macrophages through Hexokinase 2.

T cell immunoglobulin and mucin domain-3 (Tim-3), an immune checkpoint molecule, plays critical roles in maintaining innate immune homeostasis; however, the mechanisms underlying these roles remain to be determined. Here, we determined that Tim-3 controls glycolysis in macrophages and thus contributes to phenotype shifting. Tim-3 signal blockade significantly increases lactate production by macrophages, but does not influence cell proliferation or apoptosis. Tim-3 attenuates glucose uptake by inhibiting hexokinase 2 (HK2) expression in macrophages. Tim-3-mediated inhibition of macrophage glycolysis and the expression of proinflammatory cytokines, tumour necrosis factor (TNF)-α and interleukin (IL)-1ß are reversed by HK2 silencing. Finally, we demonstrated that Tim-3 inhibits HK2 expression via the STAT1 pathway. We have thus discovered a new way by which Tim-3 modulates macrophage function.

Tim-3 Promotes Listeria monocytogenes Immune Evasion by Suppressing Major Histocompatibility Complex Class I.

BACKGROUND: T-cell immunoglobulin and mucin protein 3 (Tim-3) is an immune checkpoint inhibitor that has therapeutic implications for many tumors and infectious diseases. However, the mechanisms by which Tim-3 promotes immune evasion remain unclear. METHODS: In this study, we demonstrated that Tim-3 inhibits the expression of major histocompatibility complex class I (MHC-I) in macrophages at both the messenger ribonucleic acid and protein levels by inhibiting the STAT1-NLRC5 signaling pathway. RESULTS: As a result, MHC-I-restricted antigen presentation by macrophages was inhibited by Tim-3 both in vitro and in a Listeria monocytogenes infection model in vivo. Systemic overexpression of Tim-3 or specific knockout of Tim-3 in macrophages significantly attenuated or enhanced CD8+ T-cell activation and infection damage in L monocytogenes-infected mice, respectively. CONCLUSIONS: Thus, we identified a new mechanism by which Tim-3 promotes L monocytogenes immune evasion. Further studies on this pathway might shed new light on the physio-pathological roles of Tim-3 and suggest new approaches for intervention.

Monoclonal antibody against human Tim-3 enhances antiviral immune response.

T cell immunoglobulin and mucin domain protein 3 (Tim-3) is an immune checkpoint inhibitor in T cells and innate immune cells. The deregulated upregulation of Tim-3 is related to immune exhaustion in tumour and viral infection. To overcome Tim-3-mediated immune tolerance, we developed a novel monoclonal antibody against human Tim-3 (L3G) and investigated its roles in inhibiting Tim-3 signalling and overcoming immune tolerance in T cells and monocytes/macrophages. The administration of L3G to cultured peripheral blood mononuclear cells (PBMCs) significantly increased the production of IFN-γ and IL-2 and the expression of type I interferon. The administration of L3G also increased the production of IFN-γ, IL-8 and type I interferon in U937 cells and primary monocytes. We investigated the mechanisms by which L3G enhances pro-inflammatory cytokine expression, and our data show that L3G enhances STAT1 phosphorylation in both monocytes/macrophages and T cells. Finally, in an H1N1 infection model of PBMCs and U937 cells, L3G decreased the viral load and enhanced the expression of interferon. Thus, we developed a functional antibody with therapeutic potential against Tim-3-mediated infection tolerance.

Gm40600 suppressed SP 2/0 isograft tumor by reducing Blimp1 and Xbp1 proteins.

BACKGROUND: Multiple myeloma (MM), characterized by cancerous proliferation of plasmablasts (PB) and plasma cells (PC), remains incurable in many patients. Differentially expressed molecules between MM PCs and healthy PCs have been explored in order to identify novel targets for treating MM. In the present study, we searched for novel MM therapeutic targets by comparing mRNA expression patterns between the Mus musculus myeloma plasmablast-like SP 2/0 cell line and LPS-induced PB/PC. METHODS: Gene expression profiles of LPS-induced PB/PC and SP 2/0 cells were determined using RNA-sequencing. A predicted gene (Gm40600) was found to be expressed at a low level in SP 2/0 cells. To study the role of Gm40600 in malignant PC, Gm40600 cDNA was cloned into a lentiviral vector (LV201) containing a puromycin selectable marker that was then transfected into SP 2/0 cells. Stable Gm40600-expressing SP 2/0 cells were selected using puromycin. The effect of Gm40600 on SP 2/0 cell proliferation, cell cycle/apoptosis, and tumor progression was assessed by cell counting kit-8 (CCK8), flow cytometry (FACS), and the SP 2/0 isograft mouse model, respectively. The effect of Gm40600 on mRNA and protein expression was evaluated by RNA-sequencing and western blotting, respectively. RESULTS: We found that SP 2/0 cells expressed lower level of Gm40600 mRNA as compared to LPS-induced PB/PC. Overexpression of Gm40600 significantly suppressed SP 2/0 cell proliferation and isograft tumor progression in an isograft mouse model by promoting apoptosis. In addition, Gm40600 overexpression suppressed transcription of the gene encoding Bcl2. Gm40600 overexpression also reduced the expression of PC-associated transcription factors Blimp1 and Xbp1, which promote transcription of the gene that encodes Bcl2. CONCLUSIONS: Gm40600 reduced SP 2/0 cell proliferation and isograft tumor growth and progression by suppressing Blimp1 and Xbp1-mediated Bcl2 transcription to induce apoptosis. Thus, regulation of a human homolog of Gm40600, or associated factors, may be a potential therapeutic approach for treating MM.

Negative regulation of Nod-like receptor protein 3 inflammasome activation by T cell Ig mucin-3 protects against peritonitis.

The Nod-like receptor protein 3 (NLRP3) inflammasome plays roles in host defence against invading pathogens and in the development of autoimmune damage. Strict regulation of these responses is important to avoid detrimental effects. Here, we demonstrate that T cell Ig mucin-3 (Tim-3), an immune checkpoint inhibitor, inhibits NLRP3 inflammasome activation by damping basal and lipopolysaccharide-induced nuclear factor-κB-mediated up-regulation of NLRP3 and interleukin-1ß during the priming step and basal and ATP/lipopolysaccharide-induced ATP production, K+ efflux, and reactive oxygen species production during the activation step. Residues Y256/Y263 in the C-terminal region of Tim-3 are required for these inhibitory effects on the NLRP3 inflammasome. In mice with alum-induced peritonitis, blockade of Tim-3 exacerbates peritonitis by overcoming the inhibitory effect of Tim-3 on NLRP3 inflammasome activation, while transgenic expression of Tim-3 attenuates inflammation by inhibiting NLRP3 inflammasome activation. Our results show that Tim-3 is a critical negative regulator of NLRP3 inflammasome and provides a potential target for intervention of diseases with uncontrolled inflammasome activation.

Treatment of Paraquat-Induced Lung Injury With an Anti-C5a Antibody: Potential Clinical Application.

OBJECTIVES: Complement activation product C5a plays a critical role in systemic inflammatory response syndrome induced by viruses, bacteria, and toxic agents including paraquat poisoning. This study is to explore the efficiency of anti-C5a-based intervention on systemic inflammatory responses induced by paraquat poisoning. DESIGN: Study of cynomolgus macaque model and plasma from paraquat-poisoning patients. SETTING: Laboratory investigation. SUBJECTS: Cynomolgus macaque (n = 12) and samples of plasma from patients (n = 16). INTERVENTIONS: The neutralizing antihuman C5a antibody (IFX-1) was administered to investigate the new treatment strategy for paraquat-induced systemic inflammatory responses in cynomolgus macaque model. In addition, C5a activation in plasma of paraquat patients was blocked by IFX-1 to investigate the blockade role of anti-C5a antibody in activation of inflammatory cells. MEASUREMENTS AND MAIN RESULTS: Dysregulated complement activation and the subsequent cytokine storm were found in patients with acute lung injury and in a primate model of paraquat poisoning. Targeted inhibition of C5a by IFX-1 led to marked alleviation of systemic inflammatory responses and multiple organ damage in the primate model. In addition, blockade of C5a activity in plasma from patients completely inhibited activation of CD11b on blood granulocytes from normal donors, suggesting that IFX-1 may alleviate the excessive activation of inflammatory responses and have clinical utility for patients with acute lung injury. CONCLUSIONS: Anti-C5a antibodies such as IFX-1 may be used as effective therapeutics for treatment of those suffering from systemic inflammatory responses induced by chemical poisoning like paraquat.

Increased mTOR cancels out the effect of reduced Xbp-1 on antibody secretion in IL-1α-deficient B cells.

IL-1α in vitro promotes immunoglobulin secretion by inducing proliferation of mature B cells, whereas IL-1α deficiency has no effect on in vivo antibody production. However, the reason IL-1α deficiency does not reduce in vivo antibody production is still unclear. In this study, we found that similar as in vivo data, IL-1α deficiency did not affect antibody production in in vitro LPS-stimulated B cells. Surprisingly, LPS-stimulated IL-1α-/- B cells reduced a key antibody production-related transcription factor X-box binding protein 1 (Xbp-1) expression. Furthermore, we found that IL-1α deficiency up-regulated mTOR expression, which bypassed Xbp-1 for immunoglobulin secretion. Finally, we showed that Xbp-1 suppressed mTOR expression, whereas mTOR suppressed the activation of Xbp-1 promoter via JunB. Together, these data suggest that IL-1a deficiency reduced Xbp-1 and up-regulated mTOR. This may explain why IL-1α deficiency has no effect on antibody production.

BC094916 suppressed SP 2/0 xenograft tumor by down-regulating Creb1 and Bcl2 transcription.

BACKGROUND: Both multiple myeloma (MM) and systemic lupus erythematosus (SLE) are associated with abnormal production of plasma cells, although their pathological mechanism of each disease is different. The main characteristic of both diseases is uncontrolled differentiation of B cells into plasmablast/plasma cells. Despite continuous research on prognostic factors and the introduction of new agents for MM and SLE, treatments still do not exist for controlling plasmablast/plasma cells. Thus, it is necessary to identify novel therapeutic targets of plasmablast/plasma cells. Because of its plasmablast-like characteristics, the mus musculus myeloma SP 2/0 cell line was used in this study to test the effect of a novel therapeutic agent (BC094916 overexpression) on plasmablast/plasma cells. METHODS: We first determined gene expression profiles of plasma cells using Affymetrix microarrays and RNA-sequencing. The effect of BC094916 on SP 2/0 cell proliferation, cell cycle, and apoptosis was determined by CCK8 and fluorescence-activated cell sorting. The SP 2/0 xenograft mouse model was used to assess the impact of BC094916 on tumor progression. The luciferase reporter system was used to evaluate the effect of BC094916 on Creb1 and Bcl2 transcription. RESULTS: We found that BC094916 mRNA was decreased in plasma cells. The mouse myeloma cell line SP 2/0 expressed low levels of BC094916 mRNA, whereas BC094916 overexpression suppressed SP 2/0 cell proliferation by inducing apoptosis. BC094916 overexpression suppressed tumor progression in the SP 2/0 xenograft mouse model. We also found that BC094916 mediate apoptosis by suppressing transcription of the Creb1 and Bcl2 genes, which promote the transcription of eukaryotic translation initiation and elongation factor genes. CONCLUSIONS: BC094916 overexpression suppressed Creb1 and Bcl2 transcription to induce cell apoptosis, which suppressed SP 2/0 proliferation and xenograft tumor progression. Thus, BC094916 overexpression may be a potential therapeutic agent for treatment of MM and autoimmune diseases such as SLE.

CD19 regulates ADAM28-mediated Notch2 cleavage to control the differentiation of marginal zone precursors to MZ B cells.

As the first line of defence, marginal zone (MZ) B cells play principal roles in clearing blood-borne pathogens during infection and are over-primed in autoimmune diseases. However, the basic mechanisms underlying MZ B-cell development are still unclear. We found here that CD19 deficiency blocked the differentiation of marginal zone precursors (MZP) to MZ B cells, whereas CD19 expression in CD19-deficient MZP rescues MZ B-cell generation. Furthermore, CD19 regulates Notch2 cleavage by up-regulating ADAM28 expression in MZP. Finally, we found that CD19 suppressed Foxo1 expression to promote ADAM28 expression in MZP. These results suggest that CD19 controls the differentiation of MZP to MZ B cells by regulating ADAM28-mediated Notch2 cleavage. Thus, we demonstrated the basic mechanisms underlying the differentiation of MZP to MZ B cells.