Hongye Fan

Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis.

Mesenchymal stem cells (MSCs) have been used experimentally for treating inflammatory disorders, partly due to their immunosuppressive properties. Although interleukin-1β (IL-1β) is one of the most important inflammatory mediators, growing evidence indicates that IL-1β signaling elicits the immunosuppressive properties of MSCs. However, it remains unclear how IL-1β signaling accomplishes this activity. Here, we focus on the therapeutic efficacy of IL-1β-primed MSCs in the dextran sulfate sodium (DSS)-induced colitis model, in addition to the underlining mechanisms. We first found that IL-1β-primed MSCs, without any observable phenotype change in vitro, significantly attenuated the development of DSS-induced murine colitis. Moreover, IL-1β-primed MSCs modulated the balance of immune cells in the spleen and the mesenteric lymph nodes (MLNs) through elevating cyclooxygenase-2 (COX-2), IL-6 and IL-8 expression and influencing the polarization of peritoneal macrophages. Importantly, IL-1β-primed MSCs possessed an enhanced ability to migrate to the inflammatory site of the gut via upregulation of chemokine receptor type 4 (CXCR4) expression. In summary, IL-1β-primed MSCs have improved efficacy in treating DSS-induced colitis, which at least partly depends on their increased immunosuppressive capacities and enhanced migration ability.

17β-estradiol induces CD40 expression in dendritic cells via MAPK signaling pathways in a minichromosome maintenance protein 6–dependent manner

OBJECTIVE The human immune system exhibits sexual dimorphism in autoimmune diseases such as systemic lupus erythematosus (SLE). Female sex hormones, including 17β-estradiol, are strongly implicated in the gender bias in SLE. CD40 is a costimulatory molecule and plays a crucial role in modulating the immune response of effector cells. We have previously shown that 17β-estradiol up-regulated CD40 expression and altered minichromosome maintenance protein 6 (MCM6) gene expression in dendritic cells (DCs). The mechanism of the correlation between CD40 and MCM6 in the presence of 17β-estradiol remains unknown. This study was undertaken to elucidate this mechanism and to explain the role of MCM6 in the gender bias in SLE. METHODS Bone marrow-derived DCs transfected with small interfering RNA (siRNA) for MCM6 were treated with 17β-estradiol in the absence or presence of CpG. The expression levels of costimulatory molecules, activity of MAPKs, and levels of MCM6 protein were measured. Moreover, the functions of DCs, including proliferation, apoptosis, endocytosis, and cytokine production, were analyzed. In addition, levels of messenger RNA for MCM6 were detected in DCs purified from SLE patients. RESULTS Regardless of the presence or absence of CpG, 17β-estradiol induced CD40 expression via the activation of p38 and JNK, but not ERK. The activation of p38 and JNK enhanced MCM6 expression, which then induced CD40 expression. Suppression of MCM6 in DCs abolished the up-regulation of 17β-estradiol-induced CD40 expression. Importantly, MCM6 expression was significantly increased in SLE patients compared with healthy controls. CONCLUSION Our findings indicate that 17β-estradiol induces CD40 expression in DCs via p38 and JNK MAPKs in an MCM6-dependent manner. MCM6 may be a critical mediator of sex-based differences in autoimmune disease.

Mesenchymal Stem Cells Ameliorate Th1-Induced Pre-Eclampsia-Like Symptoms in Mice via the Suppression of TNF-α Expression

Pre-eclampsia (PE) is thought to be a pregnancy-induced autoimmune disease. Despite several strategies carried out for targeting specific factors relevant to its pathogenesis, PE remains potentially fatal to some patients. Here, we reported a way to isolate mesenchymal stem cells (MSCs) from decidua. The MSCs not only exhibited differentiation and self-renewal capacities, they also possessed immunomodulatory functions and secreted some soluble mediators including IL-6, TGF-β, IDO, VEGF and COX-2. Most importantly, the MSCs were specifically provided with the ability to suppress T cells proliferation by IDO in response to inflammatory cytokine IFN-γ. Moreover, we developed a Th1 cell-induced PE mouse model which displayed a high level of pathogenesis factor TNF-α. Strikingly, MSCs-based therapy significantly ameliorated both clinical and histopathological severity of PE symptoms including decreasing the blood pressure and proteinuria, suppressing glomerulonephritis, protecting the feto-placental development. The therapy also reversed abnormal TNF-α expression in uterine and splenic lymphocytes. These data suggest that MSCs may ameliorate Th1-induced PE-like symptoms in mice via the suppression of TNF-α and MSCs-based therapy may provide a potential novel method for PE.

Progesterone Enhances Immunoregulatory Activity of Human Mesenchymal Stem Cells Via PGE2 and IL‐6

Progesterone (P4) plays a central role in the establishment and maintenance of pregnancy. It also has profound effects on the regulation of immune responses. Mesenchymal stem cells (MSCs), which are thought to have the ability to modulate immunocyte activation, are present in human endometrium and deciduas and highly express progesterone receptor (PR). Especially, during pregnancy, both P4 and MSCs are present and regulatively changed at the fetal–maternal interface, but the effect of P4 on the MSCs remains unknown. Therefore, in this study, we investigated the effects of P4 on the immunomodulatory ability of MSCs and the underlying mechanisms.

Gender differences of B cell signature in healthy subjects underlie disparities in incidence and course of SLE related to estrogen.

The aim of the present study was to investigate mechanism of the gender differences of B cells. The results showed that 358 differential gene expressions (DEGs) were displayed between healthy females and males. Compared with male, 226 and 132 genes were found to be up- and downregulated in the female. 116 genes displayed possible correlation with estrogen. Moreover, the upregulated DEGs (Cav1, CD200R1, TNFRSF17, and CXCR3) and downregulated DEGs (EIF1AY and DDX3Y) in healthy female may be involved in gender predominance of some immune diseases. Furthermore, signaling pathway analysis for estrogen-relevant DEGs showed that only 26 genes were downregulated in SLE female versus SLE male, of which expressions of 8 genes had significant difference between SLE females and SLE males but are having nonsignificant difference between healthy females and healthy males. Except for the 5 Y-chromosome-related genes or varients, only 3 DEGs (LTF, CAMP, and DEFA4) were selected and qRT-PCR confirmed that the expressions of LTF and CAMP decreased significantly in B cells from female SLE patients. These data indicated that the gender differences were existent in global gene expression of B cells and the difference may be related to estrogen.

Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B-cell hyperreactivity. The Toll-like receptor 7 (TLR7) signaling pathway is abnormally activated in SLE B cells. CyclinD3 (CCND3) plays an important role in B-cell proliferation, development, and differentiation. Although previous studies focused on the B cell-intrinsic role of TLR7 for the development of spontaneous germinal centers, the influence of TLR7 on CCND3 in SLE B cells is still not clear. Here, we used a B-cell profiling chip and found that CCND3 was related to SLE and significantly elevated in SLE B cells. Moreover, we determined that the expression level of CCND3 was higher, while miR-15b was significantly lower in the B cells from SLE patients and B6.MRL-Faslpr/J lupus mice compared to normal subjects. Furthermore, we demonstrated that the activation of TLR7 dramatically increased CCND3 expression but significantly decreased miR-15b in B cells in vitro and we identified that CCND3 is a direct target of miR-15b. To further confirm our results, we established another lupus model by topically treating C57BL/6 (B6) mice with the TLR-7 agonist imiquimod (IMQ) for 8 weeks according to the previously described protocol. Expectedly, topical treatment with IMQ also significantly increased CCND3 and decreased miR-15b in B cells of B6 mice. Taken together, our results identified that the activation of TLR7 increased CCND3 expression via the downregulation of miR-15b in B cells; thus, these findings suggest that extrinsic factor-induced CCND3 expression may contribute to the abnormality of B cell in SLE.

17β-Estradiol enhances response of mice spleen B cells elicited by TLR9 agonist.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against nucleic acid-associated antigens. B cells play cardinal roles in SLE. Many evidences have proved estrogen contribute to the gender bias in SLE and 17β-estradiol (E2) could accelerate the disease by regulating B cells. On the other hand, B cells express TLR9 which recognized dsDNA and played a critical role in SLE. However, the crosstalk between estrogen and TLR9 in B cells remains unknown. So we investigated the E2 effect in the presence of the TLR9 ligand CpG on mice spleen B cells. We found that the up-regulation of cell viability, life-span, co-stimulation molecules (CD40, CD86) expression, IgM secretion, TLR9 and MCM6 expression were more significant than CpG ODN or E2 stimulated alone. It may provide a new way to investigate the mechanism of how E2 modulate the B cells function in lupus.

Gender differences of B cell signature related to estrogen-induced IFI44L/BAFF in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) possesses a gender-dependent incidence characterized by a male/female ratio 1:9. B-cell, a vital part of the immune system, plays an important role in pathogenesis of SLE. Thus, we hypothesize that gender differences of B cells may exist in SLE and relate to the onset and the progression of SLE. Here, we showed that the genes expression pattern is similar between healthy female and male. However, SLE female and SLE male showed more upregulated genes, in which the trendline of SLE male is higher than that of SLE female. The most differentially expressed genes between SLE male patients and female patients are only on two chromosomes. While the differentially expressed genes between healthy male and female are distributed on several chromosomes. There are more differentially expressed genes in SLE male vs healthy male than these in SLE female vs healthy female. OAS3, RGS13, STAG3, IFI44L, STS-1, FERIL14, ZBTB16, USP18, USP41, RSAD2, FKBP5, IL1R2, DNAPTP6 and ILI27, which top 14 significantly upregulated mRNAs in SLE patients compared with healthy donors, showed different expression pattern in gender-based analyses. Furthermore, we revealed that this difference may be related to estrogen-induced IFI44L/BAFF. Therefore, we conclude that the diagnosis and treatment of these immune-related diseases should consider the baseline gender-related differences.

TLR7, a third signal for the robust generation of spontaneous germinal center B cells in systemic lupus erythematosus

TLR7, a third signal for the robust generation of spontaneous germinal center B cells in systemic lupus erythematosus