Interleukin‐12 family cytokines have emerged as critical regulators of immunity with some members (IL‐12, IL‐23) associated with disease pathogenesis while others (IL‐27, IL‐35) mitigate autoimmune diseases. Each IL‐12 family member is comprised of an α and a β chain, and chain‐sharing is a key feature. Although four bona fide members have thus far been described, promiscuous chain‐pairing between alpha (IL‐23p19, IL‐27p28, IL‐12/IL‐35p35) and beta (IL‐12/IL‐23p40, IL‐27/IL‐35Ebi3) subunits, predicts six possible heterodimeric IL‐12 family cytokines. Here, we describe a new IL‐12 member composed of IL‐23p19 and Ebi3 heterodimer (IL‐39) that is secreted by LPS‐stimulated B cells and GL7⁺ activated B cells of lupus‐like mice. We further show that IL‐39 mediates inflammatory responses through activation of STAT1/STAT3 in lupus‐like mice. Taken together, our results show that IL‐39 might contribute to immunopathogenic mechanisms of systemic lupus erythematosus, and could be used as a possible target for its treatment.

NLRP3 inflammasome activation plays an important role in diabetic cardiomyopathy (DCM), which may relate to excessive production of reactive oxygen species (ROS). Gypenosides (Gps), the major ingredients of Gynostemma pentaphylla (Thunb.) Makino, have exerted the properties of anti‐hyperglycaemia and anti‐inflammation, but whether Gps improve myocardial damage and the mechanism remains unclear. Here, we found that high glucose (HG) induced myocardial damage by activating the NLRP3 inflammasome and then promoting IL‐1β and IL‐18 secretion in H9C2 cells and NRVMs. Meanwhile, HG elevated the production of ROS, which was vital to NLRP3 inflammasome activation. Moreover, the ROS activated the NLRP3 inflammasome mainly by cytochrome c influx into the cytoplasm and binding to NLRP3. Inhibition of ROS and cytochrome c dramatically down‐regulated NLRP3 inflammasome activation and improved the cardiomyocyte damage induced by HG, which was also detected in cells treated by Gps. Furthermore, Gps also reduced the levels of the C‐reactive proteins (CRPs), IL‐1β and IL‐18, inhibited NLRP3 inflammasome activation and consequently improved myocardial damage in vivo. These findings provide a mechanism that ROS induced by HG activates the NLRP3 inflammasome by cytochrome c binding to NLRP3 and that Gps may be potential and effective drugs for DCM via the inhibition of ROS‐mediated NLRP3 inflammasome activation.

We have previously demonstrated that exosomes from dendritic cells (DCs) secreting TGF‐β1 (sTGF‐β1‐EXOs) delay the development of murine inflammatory bowel disease (IBD). In this study, we isolated exosomes from DCs expressing membrane‐associated TGF‐β1 (mTGF‐β1‐EXOs) and found mTGF‐β1‐EXOs had more potent immunosuppressive activity than sTGF‐β1‐EXOs in vitro. Treatment of mice with mTGF‐β1‐EXOs inhibited the development and progression of myelin oligodendrocyte glycoprotein (MOG) peptide‐induced EAE even after disease onset. Treatment of mice with mTGF‐β1‐EXOs also impaired Ag‐specific Th1 and IL‐17 responses, but promoted IL‐10 responses ex vivo. Treatment with mTGF‐β1‐EXOs decreased the frequency of Th17 cells in EAE mice, which might be associated with the down‐regulation of the p38, ERK, Stat3, and NF‐κB activation and IL‐6 expression in DCs. Treatment with mTGF‐β1‐EXOs maintained the regulatory capacity of Treg cells, and adoptive transfer of CD4⁺Foxp3⁺ Treg cells from mTGF‐β1‐EXO‐treated EAE mice dramatically prevented the development of EAE in the recipients. Moreover, treatment with mTGF‐β1‐EXOs from C57BL/6 mice effectively prevented and inhibited proteolipid protein (PLP) peptide‐induced EAE in BALB/c mice. These results indicate that mTGF‐β1‐EXOs possess powerful immunosuppressive ability and can effectively inhibit the development and progression of EAE in different strains of mice.

Human ABCG2, a member of the ATP-binding cassette transporter superfamily, represents a promising target for sensitizing MDR in cancer chemotherapy. Although lots of ABCG2 inhibitors were identified, none of them has been tested clinically, maybe because of several problems such as toxicity or safety and pharmacokinetic uncertainty of compounds with novel chemical structures. One efficient solution is to rediscover new uses for existing drugs with known pharmacokinetics and safety profiles. Here, we found the new use for sorafenib, which has a dual-mode action by inducing ABCG2 degradation in lysosome in addition to inhibiting its function. Previously, we reported some novel dual-acting ABCG2 inhibitors that showed closer similarity to degradation-induced mechanism of action. On the basis of these ABCG2 inhibitors with diverse chemical structures, we developed a pharmacophore model for identifying the critical pharmacophore features necessary for dual-acting ABCG2 inhibitors. Sorafenib forms impressive alignment with the pharmacophore hypothesis, supporting the argument that sorafenib is a potential ABCG2 inhibitor. This is the first article that sorafenib may be a good candidate for chemosensitizing agent targeting ABCG2-mediated MDR. This study may facilitate the rediscovery of new functions of structurally diverse old drugs and provide a more effective and safe way of sensitizing MDR in cancer chemotherapy. Mol Cancer Ther; 11(8); 1693–702. ©2012 AACR.

Regulatory B cells (Bregs) are a functionally defined B cell subset, and IL-10 is crucial for the suppressive functions of Bregs. However, little is known regarding how IL-10 production is regulated in B cells. To explore the mechanisms by which IL-10 is regulated in B cells, we used mRNA microarrays to screen for molecules that are upregulated in IL-10-producing B cells and identified RNA-binding motif protein 47 (Rbm47) as a post-transcriptional regulator. Rbm47 was found to promote IL-10 production in B cells. We found that Rbm47 promotes the stability of IL-10 mRNA by binding to AU-rich elements in the 3′ untranslated region of Il10 mRNA. In addition, we demonstrated that the overexpression of Rbm47 enabled B cells to facilitate Foxp3⁺ regulator T-cell induction and reduce the severity of DSS-induced ulcerative colitis. Taken together, these results suggest that Rbm47 plays an important role in regulating IL-10 at the post-transcriptional level, thus promoting the regulatory functions of B cells. The findings presented in this study not only increase our understanding of the post-translational regulation of IL-10 in B cells but also identify a novel strategy for the potential application of Bregs.

TRAIL blockade limits cardiac cell death and reduces inflammation to improve cardiac function after myocardial infarction in rats, pigs, and monkeys.