Suppressed IL-6 Production Research Articles

CD38 in SLE CD4 T cells promotes Ca2+ flux and suppresses interleukin-2 production by enhancing the expression of GM2 on the surface membrane.

CD38 has emerged as a potential therapeutic target for patients with systemic lupus erythematosus (SLE) but it is not known whether CD38 alters CD4+ T cell function. Using primary human T cells and CD38-sufficient and CD38-deficient Jurkat T cells, we demonstrate that CD38 shifts the T cell lipid profile of gangliosides from GM3 to GM2 by upregulating B4GALNT1 in a Sirtuin 1-dependent manner. Enhanced expression of GM2 causes ER stress by enhancing Ca2+ flux through the PLCγ1-IP3 pathway. Interestingly, correction of the calcium overload by an IP3 receptor inhibitor, but not by a store-operated calcium entry (SOCE) inhibitor, improves IL-2 production by CD4+ T cells in SLE. This study demonstrates that CD38 affects calcium homeostasis in CD4+ T cells by controlling cell membrane lipid composition that results in suppressed IL-2 production. CD38 inhibition with biologics or small drugs should be expected to benefit patients with SLE.

ARID5B is a negative modulator of IL-6 production in rheumatoid arthritis synovial fibroblasts

Recent single-cell RNA-sequencing analysis of rheumatoid arthritis (RA) synovial tissues revealed the heterogeneity of RA synovial fibroblasts (SFs) with distinct functions such as high IL-6 production. The molecular mechanisms responsible for high IL-6 production will become a promising drug target of RASFs to treat RA. In this study, we performed siRNA screening of 65 transcription factors (TFs) differentially expressed among RASF subsets to identify TFs involved in IL-6 production. The siRNA screening identified 7 TFs including ARID5B, a RA risk gene, that affected IL-6 production. Both long and short isoforms of ARID5B were expressed and negatively regulated by TNF-α in RASFs. The siRNA knockdown and lentiviral overexpression of long and short isoforms of ARID5B revealed that the long isoform suppressed IL-6 production stimulated with TNF-α. eQTL analysis using 58 SFs demonstrated that RA risk allele, rs10821944, in intron 4 of the ARID5B gene had a trend of eQTL effects to the expression of long isoform of ARID5B in SFs treated with TNF-α. ARID5B was found to be a negative modulator of IL-6 production in RASFs. The RA risk allele of ARID5B intron may cause high IL-6 production, suggesting that ARID5B will become a promising drug target to treat RA.

Sesamin Enhances Apoptosis of Activated T cells by physically Interacting with MCL-1 and Shows Therapeutic Effect on Allergic Dermatitis

Sesamin is lignans mainly found in sesame seeds and oil. Previous studies have demonstrated that sesamin has potent pharmacological activities including anti-inflammatory, antioxidative, and cholesterol-and lipid-lowering. Detailed studies performed with sesamin revealed that it possesses anti-proliferative and pro-apoptotic properties that could potentially be used to kill tumors. Nevertheless T cell-mediated disorders usually occur when over-activated T cells are proliferative and less apoptotic, however, it is unknown whether sesamin suppresses T cell activation with underlying mechanism related to proliferation and apoptosis. In the present study, we evaluate whether sesamin upregulates apoptosis on activated T cells and improves T cell-mediated disease. First of all, we confirmed that sesamin suppresses IL-2 production and CD69 expression from activated T cells by quantitative PCR, ELISA and flow cytometry. In silico analysis showed that Myeloid cell leukemia 1 (MCL-1) is predicted to physically interact with sesamin in T cells. According to the in silico prediction, pulldown assay using sepharose4B beads and western blot results showed that treatment with sesamin physically binds to MCL-1 in T cells and regulates S56 phosphorylation level of MCL-1 which represents activity of MCL-1 in activated T cells. Moreover, inhibition of MCL-1 activity by sesamin blocked heterodimer interaction between MCL-1 and BAK in activated T cells by co-immunoprecipitation assay. These results led sesamin to selectively induce cell death pathway only in activated T cells. Oral administration of sesamin alleviated the symptoms of dinitrochlorobenzene (DNCB)/mite extract-induced AD, including ear thickness, mRNA levels of pro-atopic cytokines on the ear lesions of sesamin-treated AD mice. Therefore, these results suggest that sesamin has a therapeutic potential for treating T-cell mediated disease through modulating MCL-1 activity on activated T cells. This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(2021R1I1A1A01059119). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Lactobacillus plantarum isolated from kimchi regulates inflammation by increasing interleukin-10 secretion by antigen-presenting cells, leading to diminishing of STAT5 phosphorylation in Th2 cells.

The relationship between allergic inflammation and gut microbiota has been elucidated, and the effect of probiotics on immune disorders has been studied as well. Identifying the role of probiotics in individual diseases and immune responses and selecting and applying specific microorganisms based on these findings can be an effective strategy for using probiotics. Herein, lactobacilli isolated from kimchi were investigated in depth, focusing on their immune regulatory effects and the mechanisms involved. Lactic acid bacteria (LAB) effectively diminished the increased secretion of T helper 2 cytokines, such as IL-4, IL-5, and IL-13, from ovalbumin (OVA)-sensitized mouse splenocytes. The gene expression of GATA3, IL-4, IL-5, IL-9, and IL-13 was confirmed to be regulated by LAB. LAB also suppressed IL-2 production and STAT5 phosphorylation. An IL-10-neutralizing antibody attenuated these effects, indicating that LAB-induced upregulation of IL-10 in antigen-presenting cells was responsible at least partially for the increased IL-2 production and STAT5 phosphorylation in CD4+ T cells. In conclusion, the current study identified one immunomodulatory mechanism that allows LAB to regulate allergic immune reactions and the potential of LAB from kimchi to modulate various immune reactions.

Ginseng-Epimedii formula ameliorated experimental Sjögren’s syndrome via reducing IL-6 production

Medicinal herbs have been recently investigated to explore their therapeutic potential on autoimmune disorders, as an alternative treatment to relieve disease symptoms. Here, we sought to determine the immunomodulatory function of a Chinese medicine formula Ginseng-Epimedii (GE), constituted by Lycium barbarum, Ginseng, Eleutherococcus senticosus and Epimedium brevicornum, on mice with experimental Sjögren’s syndrome (ESS). We found that GE-treated ESS mice exhibited improved salivary gland function and decreased serum levels of autoantibodies. In line with the network pharmacology analysis, GE treatment suppressed IL-6 production by B cells and conventional dendritic cells, associated with decreased effector T cell subsets. Using co-culture assay and adoptive transfer model, we demonstrated that splenoctyes from ESS mice receiving GE treatment showed impaired capacity to drive pathogenic Th17 and T follicular helper cell differentiation. Thus, this study suggested the therapeutic potential of GE formula in treating SS, by skewing the microenvironment that unfavored effector T cell responses.

Allergenicity Modulation of Casein with the Modifications of Linearization, Cross-Linking, and Glycation via the Regulation of Th1/Th2 Homeostasis.

Casein (CN) is the primary allergenic protein in cow's milk, contributing to the worldwide escalating prevalence of food allergies. However, there remains limited knowledge regarding the effect of structural modifications on CN allergenicity. Herein, we prepared three modified CNs (mCN), including sodium dodecyl sulfate and dithiothreitol-induced linear CN (LCN), transglutaminase-cross-linked CN (TCN), and glucose-glycated CN (GCN). The electrophoresis results indicated widespread protein aggregation among mCN, causing variations in their molecular weights. The unique internal and external structural characteristics of mCN were substantiated by disparities in surface microstructure, alterations in the secondary structure, variations in free amino acid contents, and modifications in functional molecular groups. Despite the lower digestibility of TCN and GCN compared to LCN, they significantly suppressed IL-8 production in Caco-2 cells without significantly promoting their proliferation. Moreover, GCN showed the weakest capacity to induce LAD2 cell degranulation. Despite the therapeutic effect of TCN, GCN-treated mice displayed the most prominent attenuation of allergic reactions and a remarkably restored Th1/Th2 imbalance, while LCN administration resulted in severe allergic phenotypes and endotypes in both cellular and murine models. This study highlighted the detrimental effect of linear modifications and underscored the significance of glycation in relation to CN allergenicity.

Bruton's tyrosine kinase inhibition limits endotoxic shock by suppressing IL-6 production by marginal zone B cells in mice.

Sepsis is a systemic inflammatory response to a severe, life-threatening infection with organ dysfunction. Although there is no effective treatment for this fatal illness, a deeper understanding of the pathophysiological basis of sepsis and its underlying mechanisms could lead to the development of new treatment approaches. Here, we demonstrate that the selective Bruton's tyrosine kinase (Btk) inhibitor acalabrutinib augments survival rates in a lipopolysaccharide (LPS)-induced septic model. Our in vitro and in vivo findings both indicate that acalabrutinib reduces IL-6 production specifically in marginal zone B (MZ B) cells rather than in macrophages. Furthermore, Btk-deficient MZ B cells exhibited suppressed LPS-induced IL-6 production in vitro. Nuclear factor-kappa B (NF-κB) signaling, which is the downstream signaling cascade of Toll-like receptor 4 (TLR4), was also severely attenuated in Btk-deficient MZ B cells. These findings suggest that Btk blockade may prevent sepsis by inhibiting IL-6 production in MZ B cells. In addition, although Btk inhibition may adversely affect B cell maturation and humoral immunity, antibody responses were not impaired when acalabrutinib was administered for a short period after immunization with T-cell-independent (TI) and T-cell-dependent (TD) antigens. In contrast, long-term administration of acalabrutinib slightly impaired humoral immunity. Therefore, these findings suggest that Btk inhibitors may be a potential option for alleviating endotoxic shock without compromising humoral immunity and emphasize the importance of maintaining a delicate balance between immunomodulation and inflammation suppression.

RNA-Based Anti-Inflammatory Effects of Membrane Vesicles Derived from Lactiplantibacillus plantarum.

Bacteria generally release extracellular membrane vesicles (MVs), which are nanoparticles that play important roles in bacterial-bacterial and bacterial-host communication. As probiotics, lactic acid bacteria provide diverse health benefits to their hosts. In this study, we found that the Gram-positive lactic acid bacteria Lactiplantibacillus plantarum subsp. plantarum NBRC 15891 produce high amounts of MVs (LpMVs), and that LpMVs inhibit interleukin (IL)-8 production induced by lipopolysaccharide in intestinal epithelial HT29 cells. Heat- or UV-killed bacterial cells did not exhibit anti-inflammatory effects, and there was no uptake of these bacterial cells; contrarily, LpMVs were taken up into the cytoplasm of HT29 cells. Small RNAs extracted from LpMVs also suppressed IL-8 production in HT29 cells, suggesting that RNAs in the cytoplasm of bacterial cells are encapsulated in the MVs and released from the cells, which may be delivered to HT29 cells to exert their anti-inflammatory effects. In addition, administration of LpMVs to mice with dextran sodium sulfate-induced colitis alleviated colitis-induced weight loss and colon length shortening, indicating that LpMV intake is likely to be effective in preventing or ameliorating colitis.

Mesenchymal Stem/Stromal Cells Induce Myeloid-Derived Suppressor Cells in the Bone Marrow via the Activation of the c-Jun N-Terminal Kinase Signaling Pathway.

Our previous study demonstrated that mesenchymal stem/stromal cells (MSCs) induce the differentiation of myeloid-derived suppressor cells (MDSCs) in the bone marrow (BM) under inflammatory conditions. In this study, we aimed to investigate the signaling pathway involved. RNA-seq revealed that the mitogen-activated protein kinase (MAPK) pathway exhibited the highest number of upregulated genes in MSC-induced MDSCs. Western blot analysis confirmed the strong phosphorylation of c-Jun N-terminal kinase (JNK) in BM cells cocultured with MSCs under granulocyte-macrophage colony-stimulating factor stimulation, whereas p38 kinase activation remained unchanged in MSC-cocultured BM cells. JNK inhibition by SP600125 abolished the expression of Arg1 and Nos2, hallmark genes of MDSCs, as well as Hif1a, a molecule mediating monocyte functional reprogramming toward a suppressive phenotype, in MSC-cocultured BM cells. JNK inhibition also abrogated the effects of MSCs on the production of TGF-β1, TGF-β2 and IL-10 in BM cells. Furthermore, JNK inhibition increased Tnfa expression, while suppressing IL-10 production, in MSC-cocultured BM cells in response to lipopolysaccharides. Collectively, our results suggest that MSCs induce MDSC differentiation and promote immunoregulatory cytokine production in BM cells during inflammation, at least in part, through the activation of the JNK-MAPK signaling pathway.

Induction of lipopolysaccharide during pregnancy will suppress IL-6 production but not activin B

During inflammation, proinflammatory cytokines are released by various immune cells including IL-6 and activin B. Production of proinflammatory cytokines can be suppressed by estradiol and an increase in estradiol can be found in pregnancy. The aim of this study was to determine the response of IL-6 and activin b in pregnant mice through LPS induction. There were two groups of mice consisting of 8 mice which were not pregnant and 13 pregnant mice in the 2nd week. Inflammation was induced by intraperitoneal injection of LPS Escherichia coli serotype O111:B4. After 4 hours of treatment, the mice serum was collected from their intracardiac blood to measure estradiol, IL-6 and activin B using ELISA. Pregnancy significantly reduced IL-6 levels (P=0.015) but there was no significant difference in estradiol (P=0.169) and activin B (P=0.583) levels. We also found that there was no association of E2 with IL-6 (P=0.637) and activin B (P=0.306). Pregnancy influences the inflammatory response, especially IL-6. This condition can occur because during pregnancy physiological changes occur in the body which involve various complex mechanisms in regulating the immune system.

Novel anti-atrophic peptide isolated from olive flounder surimi as a nutraceutical additive against TNF-α induced muscle atrophy

Skeletal muscle atrophy has significant negative functional effects, especially on patients with inflammatory diseases. Tumor necrosis factor alpha (TNF-α) plays a crucial role in muscle pathology associated with muscle wasting and impairment of differentiation. The present study evaluated the anti-atrophic activity and related mechanism of a novel peptide (Tryptophan-Tyrosine-Lysine) derived from Olive Flounder surimi (OFSP), against TNF-α induced muscle atrophy in C2C12 myotubes. Molecular docking results showed that OFSP binds to TNF-α, inhibiting its binding to TNFR1 receptor. OFSP treatment increased the cell viability and decreased intracellular reactive oxygen species production caused by TNF-α. OFSP markedly downregulated the NF- κB pathway proteins phosphorylation, thereby inhibiting pathway activation. Furthermore, OFSP suppressed IL-6 production and expression of E2 ubiquitin ligases, atrogin-1/MAFbx and MuRF1, while increasing myogenic marker expressions. Current findings indicate that OFSP exhibits excellent anti-atrophic activity against inflammation-induced muscle atrophy, and these characteristics may be valuable in anti-atrophic functional food development.

Topical Application of a PDE4 Inhibitor Ameliorates Atopic Dermatitis through Inhibition of Basophil IL-4 Production

Phosphodiesterase 4 inhibitors have been approved for the treatment of atopic dermatitis. However, the cellular and molecular mechanisms underlying their therapeutic effect remain to be fully elucidated. In this study, we addressed this unsolved issue by analyzing the action of difamilast, a novel phosphodiesterase 4 inhibitor, on an oxazolone-induced skin allergic inflammation commonly used as a mouse model of atopic dermatitis. Topical application of difamilast ameliorated skin inflammation in association with reduced IL-4 expression even when the treatment commenced 4 days after the initiation of oxazolone challenge, showing its therapeutic effect on atopic dermatitis. IL-4-deficient mice displayed milder skin inflammation than did wild-type mice, and the difamilast treatment had little or no further therapeutic effect. This was also the case in mice depleted of basophils, predominant producers of IL-4 in the skin lesion, suggesting that difamilast may act on basophils. Notably, basophils accumulating in the skin lesion showed highly upregulated expression of Pde4b encoding the B subtype of the phosphodiesterase 4 family. Difamilast suppressed IL-4 production from basophils activated invitro, at least in part, through inhibition of ERK phosphorylation. Taken together, difamilast appeared to ameliorate atopic dermatitis inflammation through the suppression of basophil IL-4 production in the skin lesion.

Comparison of Policosanols via Incorporation into Reconstituted High-Density Lipoproteins: Cuban Policosanol (Raydel®) Exerts the Highest Antioxidant, Anti-Glycation, and Anti-Inflammatory Activity.

Reconstituted high-density lipoproteins (rHDL) containing each policosanol from Cuba (Raydel®), China (Shaanxi Pioneer), and the United States (Lesstanol®) were synthesized to compare the physiological properties of policosanol depending on sources and origin countries. After synthesis with apolipoproteinA-I (apoA-I) into rHDL, all policosanols bound well with phospholipid and apoA-I to form discoidal rHDL. An rHDL containing Cuban policosanol (rHDL-1) showed the largest rHDL particle size of around 83 ± 3 nm, while rHDL containing Chinese policosanol (rHDL-2) or American policosanol (rHDL-3) showed smaller particles around 63 ± 3 nm and 60 ± 2 nm in diameter, respectively. The rHDL-1 showed the strongest anti-glycation activity to protect the apoA-I degradation of HDL from fructose-mediated glycation: approximately 2.7-times higher ability to suppress glycation and 1.4-times higher protection ability of apoA-I than that of rHDL-2 and rHDL-3. The rHDL-1 showed the highest antioxidant ability to inhibit cupric ion-mediated LDL oxidation in electromobility and the quantification of oxidized species. A microinjection of each rHDL into a zebrafish embryo in the presence of carboxymethyllysine (CML) showed that rHDL-1 displayed the strongest anti-oxidant activity with the highest embryo survivability, whereas rHDL-2 and rHDL-3 showed much weaker protection ability, similar to rHDL alone (rHDL-0). An intraperitoneal injection of CML (250 μg) into adult zebrafish caused acute death and hyperinflammation with an elevation of infiltration of neutrophils and IL-6 production in the liver. On the other hand, a co-injection of rHDL-1 resulted in the highest survivability and the strongest anti-inflammatory ability to suppress IL-6 production with an improvement of the blood lipid profile, such as elevation of HDL-C and lowering of the total cholesterol, LDL-cholesterol, and triglyceride. In conclusion, Cuban policosanol exhibited the most desirable properties for the in vitro synthesis of rHDL with the stabilization of apoA-I, the largest particle size, anti-glycation against fructation, and antioxidant activities to prevent LDL oxidation. Cuban policosanol in rHDL also exhibited the strongest in vivo antioxidant and anti-inflammatory activities with the highest survivability in zebrafish embryos and adults via the prevention of hyperinflammation in the presence of CML.

Interaction Affinity Between Flavonoids Against Cytokines Interleukin 12 in Diabetes Mellitus

Background: Interleukin 12 can destroy insulin-producing cells, suppresses IL4 production, and can stimulate the formation of Thelper1. Quercetin is a flavonoid suitable to be chosen as the lead compound for development of safe anti-diabetic agent because in addition to its anti-diabetic effect, quercetin shows also protective effect in pancreas track.Objective: This research aims to study the docking models of certain flavonoids and to predict the quercetin and triterpene derivatives inhibition activity on Interleukin12.Method: The molecular docking method was used using the PyRx program with the Autodock Vina menu.Results: IL-12 bond affinity with Dextromethoorpene results -7 kcal/mol as the highest affinity value energy while the lowest energy is -6.1 kcal/mol, IL-12 bond affinity value with Quercetin with the highest affinity value energy is -9 kcal/mol, and the lowest energy is -7.8kcal/mol. The affinity value IL-12 bond and triterpene with the highest affinity value is energy -7 .9 kcal/mol, and the lowest energy is -7.4 kcal/molConclusion: Quercetin, has hydrogen bonds and hydrophobic bonds, where the ligand of the Quercetin compound is the ligand that has the ability to form the best interactions and bonds with IL-12 receptors (4OG9)

Stimulation of ectopically expressed muscarinic receptors induces IFN-γ but suppresses IL-2 production by inhibiting activation of pAKT pathways in primary T cells

T cell antigen receptor stimulation induces tyrosine phosphorylation of downstream signaling molecules and the phosphatidylinositol, Ras, MAPK, and PI3 kinase pathways, leading to T cell activation. Previously, we reported that the G-protein-coupled human muscarinic receptor could bypass tyrosine kinases to activate the phosphatidylinositol pathway and induce interleukin-2 production in Jurkat leukemic T cells. Here, we demonstrate that stimulating G-protein-coupled muscarinic receptors (M1 and synthetic hM3Dq) can activate primary mouse T cells if PLCβ1 is coexpressed. Resting peripheral hM3Dq+PLCβ1 (hM3Dq/β1) T cells did not respond to clozapine, an hM3Dq agonist, unless they were preactivated by TCR and CD28 stimulation which increased hM3Dq and PLCβ1 expression. This permitted large calcium and phosphorylated ERK responses to clozapine. Clozapine treatment induced high IFN-γ, CD69, and CD25 expression, but surprisingly did not induce substantial IL-2 in hM3Dq/β1 T cells. Importantly, costimulation of both muscarinic receptors plus the TCR even led to reduced IL-2 expression, suggesting a selective inhibitory effect of muscarinic receptor costimulation. Stimulation of muscarinic receptors induced strong nuclear translocation of NFAT and NFκB and activated AP-1. However, stimulation of hM3Dq led to reduced IL-2 mRNA stability which correlated with an effect on the IL-2 3'UTR activity. Interestingly, stimulation of hM3Dq resulted in reduced pAKT and its downstream pathway. This may explain the inhibitory impact on IL-2 production in hM3Dq/β1T cells. Moreover, an inhibitor of PI3K reduced IL-2 production in TCR-stimulated hM3Dq/β1 CD4 T cells, suggesting that activating the pAKT pathway is critical for IL-2 production in T cells.

Nicotine- and tar-removed cigarette smoke extract modulates the antigen presentation function of mouse bone marrow-derived dendritic cells.

Dendritic cells (DCs) take up antigens derived from pathogens such as bacteria and viruses, and from tumor cells and induce the activation of antigen-specific T cells through major histocompatibility complex (MHC)-mediated antigen presentation. Mainstream cigarette smoke extract (CSE) has various effects, and the effects of its major components, nicotine and tar, have been extensively analyzed. Recently, the physiological effects of nicotine- and tar-removed CSE (cCSE) have also been reported. However, the effects of cCSE on DC-mediated immune responses remain unknown. In this study, we found that cCSE enhanced lipopolysaccharide (LPS)-stimulated induction of the expression of MHC-I and MHC-II on the cell surface of mouse bone marrow-derived DCs (BMDCs). In contrast, cCSE suppressed the induction of CD86 induced by stimulation with curdlan and interferon-gamma (IFN-γ). In addition, cCSE suppressed the production of IL-12, IL-23, and IL-10 by LPS and curdlan stimulation. In the presence of cCSE, LPS-stimulated BMDCs showed enhanced activation of CD4 and CD8 T cells and increased IL-2 production from T cells by antigen presentation in a mixed-leukocyte reaction assay. In contrast, cCSE did not affect the activation of T cells by curdlan- or IFN-γ-stimulated BMDCs, and curdlan-stimulated BMDCs suppressed IL-17 production from T cells and enhanced IFN-γ production. These results suggest that cCSE has different effects on the activation signals induced by LPS, curdlan, and IFN-γ in BMDCs and modulates the antigen presentation function of BMDCs. This article is protected by copyright. All rights reserved.

Theophylline Attenuates BLM-Induced Pulmonary Fibrosis by Inhibiting Th17 Differentiation.

Idiopathic pulmonary fibrosis (IPF) is a chronic and refractory interstitial lung disease. Although there are two approved drugs for IPF, they were not able to completely cure the disease. Therefore, the development of new drugs is required for the effective treatment of IPF. In this study, we investigated the effect of theophylline, which has long been used for the treatment of asthma, on pulmonary fibrosis. The administration of theophylline attenuated the fibrotic changes of lung tissues and improved mechanical pulmonary functions in bleomycin (BLM)-induced pulmonary fibrosis. Theophylline treatment suppressed IL-17 production through inhibiting cytokines controlling Th17 differentiation; TGF-β, IL-6, IL-1β, and IL-23. The inhibition of IL-6 and IL-1β by theophylline is mediated by suppressing BLM-induced ROS production and NF-κB activation in epithelial cells. We further demonstrated that theophylline inhibited TGF-β-induced epithelial-to-mesenchymal transition in epithelial cells through suppressing the phosphorylation of Smad2/3 and AKT. The inhibitory effects of theophylline on the phosphorylation of Smad2/3 and AKT were recapitulated in BLM-treated lung tissues. Taken together, these results demonstrated that theophylline prevents pulmonary fibrosis by inhibiting Th17 differentiation and TGF-β signaling.

OP-1 - IL-18 induces appropriate inflammatory responses contributing placental development and fetal growth

IL-18 has pro- and anti-inflammatory effects. However, only a few studies have demonstrated its role in reproduction. Here, we developed the fetal growth restriction model mouse and examined the effect of IL-18 on fetal growth. The C57BL/6 female mice were mated with the BALB/c male mice, the anti-IL-18 neutralizing antibody was administered intraperitoneally, and the placenta and birth weight were measured. The pregnant uteri were analyzed using flow cytometry, western blotting, and immunofluorescence staining. The blockade of IL-18 significantly decreased in placenta and birth weight compared with control. The blockade of IL-18 also induced a decreased production of IFN-γ in the uterine T cells and NK cells, M2-polarization of uterine macrophages, and suppressed IL-12 production. Histologically, the vascular remodeling failure of the placental labyrinth was shown in mice with the blockade of IL-18. Importantly, we found that macrophages and smooth muscle cells are essential sources of IL-18. These findings indicate that IL-18 enhances an appropriate type 1 immune response leading to the proper placental development and fetal growth via the feedback between IFN-γ and IL-12.

Agonistic anti-CD27 antibody ameliorates EAE by suppressing IL-17 production.

CD27/CD70 costimulation enhances T-cell survival, memory formation and Th1-cell differentiation and effector function. In addition to promoting Th1 responses, CD27 signaling has been shown to exert a negative regulatory role on IL-17 production, resulting in increased sensitivity of CD27 KO mice to EAE. By inducing EAE in full CD27 KO mice, and in a novel, T-cell specific CD27 KO mouse strain (CD4-Cre x CD27flox/flox ), we demonstrate herein that CD27 engagement by its natural ligand (CD70) suppresses IL-17 production in a cell autonomous fashion. We further show that CD27 engagement by an agonistic antibody given after EAE induction or at symptom onset similarly suppresses IL-17 production by activated CD4+ T cells infiltrating the inflamed CNS while IFN-γ production was unaffected, leading to an amelioration of inflammatory-related symptoms. These findings propose CD27 costimulation as a potential candidate for therapeutic manipulation to treat autoimmune and autoinflammatory diseases characterized by excessive IL-17 production.

PPP2R2D Suppresses Effector T Cell Exhaustion and Regulatory T Cell Expansion and Inhibits Tumor Growth in Melanoma.

We had shown previously that the protein phosphatase 2A regulatory subunit PPP2R2D suppresses IL-2 production, and PPP2R2D deficiency in T cells potentiates the suppressive function of regulatory T (Treg) cells and alleviates imiquimod-induced lupus-like pathology. In this study, in a melanoma xenograft model, we noted that the tumor grew in larger sizes in mice lacking PPP2R2D in T cells (LckCreR2Dfl/fl) compared with wild type (R2Dfl/fl) mice. The numbers of intratumoral T cells in LckCreR2Dfl/fl mice were reduced compared with R2Dfl/fl mice, and they expressed a PD-1+CD3+CD44+ exhaustion phenotype. In vitro experiments confirmed that the chromatin of exhaustion markers PD-1, LAG3, TIM3, and CTLA4 remained open in LckCreR2Dfl/fl CD4 T conventional compared with R2Dfl/fl T conventional cells. Moreover, the percentage of Treg cells (CD3+CD4+Foxp3+CD25hi) was significantly increased in the xenografted tumor of LckCreR2Dfl/fl mice compared with R2Dfl/fl mice probably because of the increase in the percentage of IL-2-producing LckCreR2Dfl/fl T cells. Moreover, using adoptive T cell transfer in mice xenografted with melanoma, we demonstrated that PPP2R2D deficiency in T cells enhanced the inhibitory effect of Treg cells in antitumor immunity. At the translational level, analysis of publicly available data from 418 patients with melanoma revealed that PPP2R2D expression levels correlated positively with tumor-infiltration level of CD4 and CD8 T cells. The data demonstrate that PPP2R2D is a negative regulator of immune checkpoint receptors, and its absence exacerbates effector T cell exhaustion and promotes Treg cell expansion. We conclude that PPP2R2D protects against melanoma growth, and PPP2R2D-promoting regimens can have therapeutic value in patients with melanoma.