Soluble Cytokine Research Articles

Cytokine regulation of apoptosis-induced apoptosis and apoptosis-induced cell proliferation in vascular smooth muscle cells

Vascular smooth muscle cells (VSMCs) are the main structural cell of blood vessels, and VSMC apoptosis occurs in vascular disease, after injury, and in vessel remodeling during development. Although VSMC apoptosis is viewed as silent, recent studies show that apoptotic cells can promote apoptosis-induced compensatory proliferation (AICP), apoptosis-induced apoptosis (AIA), and migration of both local somatic and infiltrating inflammatory cells. However, the effects of VSMC apoptosis on adjacent VSMCs, and their underlying signaling and mechanisms are unknown. We examined the consequences of VSMC apoptosis after activating extrinsic and intrinsic death pathways. VSMCs undergoing apoptosis through Fas/CD95 or the protein kinase inhibitor staurosporine transcriptionally activated interleukin 6 (IL-6) and granulocyte-macrophage colony stimulating factor (GM-CSF), leading to their secretion. Apoptosis induced activation of p38MAPK, JNK, and Akt, but neither p38 and JNK activation nor IL-6 or GM-CSF induction required caspase cleavage. IL-6 induction depended upon p38 activity, while Fas-induced GM-CSF expression required p38 and JNK. Conditioned media from apoptotic VSMCs induced VSMC apoptosis in vitro, and IL-6 and GM-CSF acted as pro-survival factors for AIA. VSMC apoptosis was studied in vivo using SM22α-DTR mice that express the diphtheria toxin receptor in VSMCs only. DT administration induced VSMC apoptosis and VSMC proliferation, and also signficantly induced IL-6 and GM-CSF. We conclude that VSMC apoptosis activates multiple caspase-independent intracellular signaling cascades, leading to release of soluble cytokines involved in regulation of both cell proliferation and apoptosis. VSMC AICP may ameliorate while AIA may amplify the effects of pro-apoptotic stimuli in vessel remodeling and disease.

The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review.

Exercise is an effective strategy for preventing and treating obesity and its related cardiometabolic disorders, resulting in significant loss of body fat mass, white adipose tissue browning, redistribution of energy substrates, optimization of global energy expenditure, enhancement of hypothalamic circuits that control appetite-satiety and energy expenditure, and decreased systemic inflammation and insulin resistance. Novel exercise-inducible soluble factors, including myokines, hepatokines, and osteokines, and immune cytokines and adipokines are hypothesized to play an important role in the body’s response to exercise. To our knowledge, no review has provided a comprehensive integrative overview of these novel molecular players and the mechanisms involved in the redistribution of metabolic fuel during and after exercise, the loss of weight and fat mass, and reduced inflammation. In this review, we explain the potential role of these exercise-inducible factors, namely myokines, such as irisin, IL-6, IL-15, METRNL, BAIBA, and myostatin, and hepatokines, in particular selenoprotein P, fetuin A, FGF21, ANGPTL4, and follistatin. We also describe the function of osteokines, specifically osteocalcin, and of adipokines such as leptin, adiponectin, and resistin. We also emphasize an integrative overview of the pleiotropic mechanisms, the metabolic pathways, and the inter-organ crosstalk involved in energy expenditure, fat mass loss, reduced inflammation, and healthy weight induced by exercise.

THU0321 URINARY T CELLS IDENTIFY ACTIVE RENAL ANCA ASSOCIATED VASCULITIS

Background:ANCA-associated vasculitis (AAV) causes necrotizing crescentic glomerulonephritis (NCGN) which is a major contributor to morbidity and mortality in AAV. Since therapy relies on cytotoxic agents with potentially severe adverse effects, a reliable non-invasive biomarker of disease activity is needed to determine the right balance between over- and undertreatment. Using the urine space as a window into the local inflammatory milieu of the kidney, quantification of urinary leukocytes using flow cytometry has become an upcoming marker of various other inflammatory kidney diseases. As recent studies have illuminated the emerging role of T regulatory (Treg) and Th17 cells in the pathogenesis of AAV, these could represent a viable non-invasive biomarker more closely displaying the underlying pathogenic processes than metabolites or epiphenomena of inflammation.Objectives:To quantify urinary T cells in active renal AAV and asses their biomarker characteristics.Methods:Using flow cytometry, T-lymphocytes and their subsets were quantified in peripheral blood and urine samples from patients with active AAV with or without NCGN, in stable remission with previous NCGN and healthy controls. Concentrations of urinary soluble metabolites and cytokines (Monocyte-attracting protein 1 (MCP-1), sCD163, sCD25 and C5a) were measured using Multiplex analysis. Results were verified in a separate validation cohort.Results:Patients with renal active AAV (n = 30) showed significantly higher urinary cell counts of total T cells, CD4+, CD8+, Treg and Th17 subsets than disease (n = 21) and healthy controls (n = 8). Patients with active renal AAV also showed a significantly higher percentage of Tregs in urine than in blood. While Tregs allowed a robust discrimination between active renal AAV and disease controls (receiver operator characteristics (ROC): area under the curve (AUC) 0.93, sensitivity 79%, specificity 95%) quantification of all T cells proved to be slightly more accurate (ROC: AUC 0.95, sensitivity 92%, specificity 95%). Soluble markers showed a slightly inferior discrimination (MCP-1 ROC: AUC 0.90, sensitivity 60%, specificity 100%, sCD163 ROC: AUC 0.92, sensitivity 96%, specificity 85%) while sCD25 and C5a were far less accurate.Conclusion:Urinary T cells are significantly elevated in active renal AAV and the increased frequency of Tregs in urine suggests active migration into inflamed glomeruli and thereby the urine rather than mere bleeding of ruptured capillaries. These cells show great potential for a non-invasive biomarker close to the local inflammatory milieu. Particularly the total count of urinary T cells showed slightly superior biomarker characteristics than previously established soluble markers. Further studies are needed to confirm these results and show potential prognostic value of these cellular markers.Disclosure of Interests:None declared

Distinct modes of action of CD40L and adaptive cytokines IL-2, IL-4/13, IL-10 and IL-21 on rainbow trout IgM+ B cells

In mammals, conventional B (B2) cells are activated within lymphoid follicles through a close relationship with T follicular helper (Tfh) cells. The interaction between CD40 expressed on B cells and its ligand (CD40L) expressed on Tfh cells is a key signal that regulates the formation of germinal centers (GCs), B cell survival, proliferation and differentiation to plasma cells (PCs) or memory cells. Additionally, certain soluble cytokines produced by T cells also strongly condition the outcome of this interaction. Despite the many differences found between fish B cells and mammalian B2 cells, and the lack of conventional GCs, rainbow trout IgM+ B cells have been shown to be stimulated by CD40L, however, whether cytokines commonly produced by T cells can further modulate this response has never been addressed to date. Thus, in this study, we determined the effects of recombinant rainbow trout adaptive cytokines interleukin 2B (IL-2B), IL-4/13A, IL-4/13B, IL-10 and IL-21 (cytokines known to activate B cells in mammals) on splenic IgM+ B cells alone or in combination with CD40L. We studied how these cytokines and CD40L cooperated to promote IgM+ B cell survival, proliferation and IgM secretion. The results obtained provide valuable information for the first time in teleost fish on how different T cell signals cooperate to activate B cells in the absence of GCs.

Modification of PLGA Scaffold by MSC-Derived Extracellular Matrix Combats Macrophage Inflammation to Initiate Bone Regeneration via TGF-β-Induced Protein.

The immunologic response toward chronic inflammation or bone regeneration via the accumulation of M1 or M2 macrophages after injury could determine the fate of biomaterial. Human umbilical cord mesenchymal stem cells (hUCMSCs) have a pivotal immunomodulatory property on directing macrophage behaviors. Herein, for the first time, 3D-printed poly(lactide-co-glycolide) (PLGA) scaffolds modified with hUCMSC-derived extracellular matrix (PLGA-ECM) are prepared by a facile tissue engineering technique with physical decellularization and 2.44±0.29mg cm-3 proteins immobilized on the PLGA-ECM contain multiple soluble cytokines with a sustainable release profile. The PLGA-ECM not only attenuates the foreign body response, but also improves bone regeneration by increasing the accumulation of M2 macrophages in an improved heterotopic transplantation model of SCID mice. Furthermore, the PLGA-ECM scaffolds with the knockdown of transforming growth factor-β-induced protein (TGFβI/βig-H3) demonstrate that M2 macrophage accumulation improved by the PLGA-ECM could be attributed to increasing the migration of M2 macrophages and the repolarization of M1 macrophages to M2 phenotype, which are mediated by multiple integrin signaling pathways involving in integrin β7, integrin α9, and integrin β1 in a TGFβI-dependent manner. This study presents an effective surface modification strategy of polymeric scaffolds to initiate tissue regeneration and combat inflammatory response by increasing M2 macrophage accumulation.

Virus-encoded cytokine and chemokine decoy receptors.

Poxviruses and herpesviruses encode secreted versions of cytokine receptors as a unique strategy to evade the host immune response. Recent advances in the field have shown the great impact of some of these proteins in immune modulation and viral pathogenesis, and have uncovered unique properties of these viral proteins not found in the cellular counterparts. These modifications inspired by viruses lead to improved immune modulatory activity of the soluble cytokine receptors, information that has been used to develop more efficient therapeutics to treat inflammatory conditions.

Comparative Analyses of the Conformational Dynamics Between the Soluble and Membrane-Bound Cytokine Receptors

Cytokine receptors receive extracellular cues by binding with cytokines to transduce a signaling cascade leading to gene transcription in cells. Their soluble isoforms, functioning as decoy receptors, contain only the ectodomain. Whether the ectodomains of cytokine receptors at the membrane exhibit different conformational dynamics from their soluble forms is unknown. Using Stimulation-2 (ST2) as an example, we performed microsecond molecular dynamics (MD) simulations to study the conformational dynamics of the soluble and the membrane-bound ST2 (sST2 and ST2). Combined use of accelerated and conventional MD simulations enabled extensive sampling of the conformational space of sST2 for comparison with ST2. Using the interdomain loop conformation as the reaction coordinate, we built a Markov State Model to determine the slowest implied timescale of the conformational transition in sST2 and ST2. We found that the ectodomain of ST2 undergoes slower conformational relaxation but exhibits a faster rate of conformational transition in a more restricted conformational space than sST2. Analyses of the relaxed conformations of ST2 further suggest important contributions of interdomain salt-bridge interactions to the stabilization of different ST2 conformations. Our study elucidates differential conformational properties between sST2 and ST2 that may be exploited for devising strategies to selectively target each isoform.

Persistent Immune Activation in HIV-1-Infected Ex Vivo Model Tissues Subjected to Antiretroviral Therapy: Soluble and Extracellular Vesicle-Associated Cytokines.

Residual immune activation after successful antiretroviral therapy (ART) in HIV-1-infected patients is associated with the increased risk of complications. Cytokines, both soluble and extracellular vesicle (EV)-associated, may play an important role in this immune activation. Ex vivo tissues were infected with X4LAI04 or R5SF162 HIV-1. Virus replicated for 16 days, or tissues were treated with the anti-retroviral drug ritonavir. Viral replication and production of 33 cytokines in soluble and EV-associated forms were measured with multiplexed bead-based assays. Both variants of HIV-1 efficiently replicated in tissues and triggered upregulation of soluble cytokines, including IL-1β, IL-7, IL-18, IFN-γ, MIP-1α, MIP-1β, and RANTES. A similar pattern was observed in EV-associated cytokine release by HIV-infected tissues. In addition, TNF-α and RANTES demonstrated a significant shift to a more soluble form compared with EV-associated cytokines. Ritonavir treatment efficiently suppressed viral replication; however, both soluble and EV-associated cytokines remained largely upregulated after 13 days of treatment. EV-associated cytokines were more likely to remain elevated after ART. Treatment of uninfected tissues with ritonavir itself did not affect cytokine release. We demonstrated that HIV-1 infection of ex vivo lymphoid tissues resulted in their immune activation as evaluated by upregulation of various cytokines, both soluble and EV-associated. This upregulation persisted despite inhibition of viral replication by ART. Thus, similar to in vivo, HIV-1-infected human tissues ex vivo continue to be immune-activated after viral suppression, providing a new laboratory model to study this phenomenon.

Toll like receptor 4 ligation promotes B7 family costimulatory molecules expression in a time and cytokine dependent fashion

Abstract Introduction The interplay between costimulatory and coinhibitory molecules allows adequate integration of instructions for T cell fate. In this study, we explored how antigen concentration and time exposition to a pathogen associated molecule pattern may modulate the expression of B7 family costimulatory molecules CD86, ICOSL, PDL1, PDL2 and the Interferon Regulatory Factor 4 in human monocyte-derived dendritic cells (MoDCs). Methods MoDCs were obtained from healthy donors. MoDCs were stimulated with different concentrations of E. coli lipopolysaccharide and stimulated for 12, 24 or 48 h. Supernatant from stimulated MoDCs were collected for soluble cytokines determination using cytometric bead arrays. Cells were collected and membrane stained with fluorochrome-conjugated monoclonal antibodies to evaluate PDL1, PDL2, CD86 and ICOSL trough flow cytometry. Intracellular staining was performed for IRF4 after cell permeabilization. Results TNF α and IL-6 were significantly increased at 12 h, while IFN-γ and IL-2 were increased at 48 h. Costimulatory molecules showed a differential expression pattern. ICOSL was preferentially incremented at 48 h post stimuli independently of concentration used. PDL1 was induced at low concentrations and short stimulation periods, maintaining their expression all along with the stimulation kinetic. PDL2 increased its expression at short time of stimulation. CD86 and IRF4 did not show statistically significant differences. Conclusion Our results suggest that costimulatory molecules have time-dependent expression profile, possibly influenced by the cytokines contained in the microenvironment and a lesser by the antigen concentration.

Effects of amotosalen treatment on human platelet lysate bioactivity: A proof-of-concept study.

Clinical application of mesenchymal stromal cells (MSCs) usually requires an in vitro expansion step to reach clinically relevant numbers. In vitro cell expansion necessitates supplementation of basal mammalian cell culture medium with growth factors. To avoid using supplements containing animal substances, human platelet lysates (hPL) produced from expired and pathogen inactivated platelet concentrates can be used in place of fetal bovine serum. However, globally, most transfusion units are currently not pathogen inactivated. As blood banks are the sole source of platelet concentrates for hPL production, it is important to ensure product safety and standardized production methods. In this proof-of-concept study we assessed the feasibility of producing hPL from expired platelet concentrates with pathogen inactivation applied after platelet lysis by evaluating the retention of growth factors, cytokines, and the ability to support MSC proliferation and tri-lineage differentiation. Bone marrow-derived MSCs (BM-MSCs) were expanded and differentiated using hPL derived from pathogen inactivated platelet lysates (hPL-PIPL), with pathogen inactivation by amotosalen/ultraviolet A treatment applied after lysis of expired platelets. Results were compared to those using hPL produced from conventional expired pathogen inactivated platelet concentrates (hPL-PIPC), with pathogen inactivation applied after blood donation. hPL-PIPL treatment had lower concentrations of soluble growth factors and cytokines than hPL-PIPC treatment. When used as supplementation in cell culture, BM-MSCs proliferated at a reduced rate, but more consistently, in hPL-PIPL than in hPL-PIPC. The ability to support tri-lineage differentiation was comparable between lysates. These results suggest that functional hPL can be produced from expired and untreated platelet lysates by applying pathogen inactivation after platelet lysis. When carried out post-expiration, pathogen inactivation may provide a valuable solution for further standardizing global hPL production methods, increasing the pool of starting material, and meeting future demand for animal-free supplements in human cell culturing.

Neutrophil expansion defines an immunoinhibitory peripheral and intratumoral inflammatory milieu in resected non-small cell lung cancer: a descriptive analysis of a prospectively immunoprofiled cohort

BackgroundThe biological underpinnings of the prognostic and predictive significance of a relative neutrophilia in patients with non-small lung cancer (NSCLC) are undefined. We sought to comprehensively examine the relationships between...

Prognostic value of serum soluble interleukin-23 receptor and related T-helper 17 cell cytokines in non-small cell lung carcinoma.

The signaling of interleukin (IL)‐23 and its receptor (IL‐23R) play a crucial role in the development of cancers. However, the clinical significance of human serum soluble IL‐23R (sIL‐23R) and its relationship with IL‐23 are still not explored in non‐small cell lung cancer (NSCLC). In our study, sIL‐23R was first identified in the serum of NSCLC patients, but not in healthy controls, by proteomics. The IL‐23R mRNA and protein were upregulated in NSCLC cell lines and tissues tested by quantitative PCR, western blot analysis and immunohistochemistry. The levels of sIL‐23R, IL‐23, and IL‐17 in 195 NSCLC patients’ serum were determined by ELISA, and high levels of sIL‐23R were significantly associated with advanced N stage (P = .039), clinical stage (P = .007), and poor 5‐year survival rate. In vitro, sIL‐23R was shown binding to IL‐23 and the balance could affect patients’ N and T stage, overall survival, and downstream cytokine IL‐17 in a potential antagonistic relationship. Although sIL‐23R, IL‐23, and IL‐17 were all associated with poor prognosis, only the sIL‐23R/IL‐23 ratio (hazard ratio, 1.945; 95% confidence interval, 1.147‐3.299; P = .014) was found to be an independent factor for prognosis. Therefore, we identified fragments of soluble cytokine receptor of IL‐23R with affinity ability to its natural ligand IL‐23 in NSCLC patients’ serum. The balance between the 2 antagonists can work as a potential prognostic serum marker.

Early Posttransplant Mobilization of Monocytic Myeloid-derived Suppressor Cell Correlates With Increase in Soluble Immunosuppressive Factors and Predicts Cancer in Kidney Recipients.

Myeloid-derived suppressor cells (MDSCs) increase in patients with cancer and are associated with poor prognosis; however, their role in transplantation is not yet understood. Here we aimed to study the MDSC effects on the evolution of kidney transplant recipients (KTRs). A cohort of 229 KTRs was prospectively analyzed. Two myeloid cells subsets. CD11bCD33CD14CD15HLA-DR (monocytic MDSC [M-MDSC]) and CD11bCD33CD14CD15HLA-DR (monocytes), were defined by flow cytometry. The suppressive capacity of myeloid cells was tested in cocultures with autologous lymphocytes. Suppressive soluble factors, cytokines, anti-HLA antibodies, and total antioxidant capacity were quantified in plasma. Pretransplant, M-MDSC, and monocytes were similar in KTRs and healthy volunteers. M-MDSCs increased immediately posttransplantation and suppressed CD4 and CD8 T cells proliferation. M-MDSCs remained high for 1 y posttransplantation. Higher M-MDSC counts at day 14 posttransplant were observed in patients who subsequently developed cancer, and KTRs with higher M-MDSC at day 14 had significantly lower malignancy-free survival. Day 14 M-MDSC >179.2 per microliter conferred 6.98 times (95% confidence interval, 1.28-37.69) more risk to develop cancer, independently from age, gender, and immunosuppression. Early posttransplant M-MDSCs were lower in patients with enhanced alloimmune response as represented by anti-HLA sensitization. M-MDSC counts correlated with higher circulatory suppressive factors arginase-1 and interleukin-10, and lower total antioxidant capacity. Early posttransplant mobilization of M-MDSCs predicts cancer and adds risk as an independent factor. M-MDSC may favor an immunosuppressive environment that promotes tumoral development.

Interferon gamma inhibits CXCL8–CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer

BackgroundPancreatic cancer (PC) is a common malignancy of the digestive system and is characterized by poor prognosis and early metastasis. Tumor immune escape plays an important role in PC progression....

Positive and negative cooperativity of TNF and Interferon-\u03b3 in regulating synovial fibroblast function and B cell survival in fibroblast/B cell co-cultures

Synovial fibroblasts (SF) were reported to produce B cell activating factor (BAFF) in response to stimulation with interferon-γ (IFN-γ) or tumor necrosis factor (TNF). However, the influence of these pro-inflammatory cytokines on other receptors/ligands of the TNF superfamily or associated cytokine receptors in SF has not been investigated yet. Here we show the differential regulation of BAFF (CD257), Fn14 (CD266), TACI (CD267), BAFF-R (CD268), BCMA (CD269), CD40 ligand (CD40L, CD154), IFN-γR (CD119), Leptin receptor (ObR, CD295), VCAM-1 (CD106) and membrane TGF-β in isolated SF and the impact of IFN-γ/TNF co-incubation on proliferation, IL-6 and IL-8 production. In addition, the impact of differentially stimulated SF on B cell survival in co-cultures was assessed. Surface cytokines and cytokine receptors were detected by flow cytometry. Soluble cytokine receptors and cytokines were quantified by ELISA. Proliferation was assessed by cell titer blue. Murine B cell survival in fibroblast/ B cell co-cultures was determined by annexin V/propidium iodide staining and flow cytometry. IFN-γ together with TNF synergistically and significantly increased the cell surface levels of BAFF, Fn14, TACI, BAFF-R, BCMA, CD40L, ObR and IFN-γR in rheumatoid arthritis SF after 72 h incubation. Soluble BAFF was only induced by IFN-γ and inhibited by TNF. Addition of TWEAK had no influence on proliferation or IL-8 production but decreased TNF-induced IL-6 production, whereas APRIL, BAFF and leptin did not modulate TNF or TNF/IFN-γ-induced proliferation or cytokine production. Proliferation was increased by TNF and further enhanced by the addition of IFN-γ. In co-culture experiments, SF stimulated with TNF/IFN but not TNF or IFN-γ alone increased shedding of VCAM-1 and expression of membrane TGFβ, which was associated with reduced survival of murine B cells. IFN-γ and TNF regulate the expression of TNF family member cytokines and associated receptors. Ligation of IFN-γR and Fn14 under pro-inflammatory conditions modulated IL-6/IL-8 production and proliferation. In B cell/SF co-cultures, the combination of TNF/IFN reduced B cell survival possibly via enhanced VCAM-1 shedding and/or increased TGF-β production. IFN-γ is necessary for the observed effects on B cell survival and SF cytokine production and emphasizes its anti-inflammatory role in rheumatoid arthritis.

The CC and CXC chemokines: major regulators of tumor progression and the tumor microenvironment.

Chemokines are a family of soluble cytokines that act as chemoattractants to guide the migration of cells, in particular of immune cells. However, chemokines are also involved in cell proliferation, differentiation, and survival. Chemokines are associated with a variety of human diseases including chronic inflammation, immune dysfunction, cancer, and metastasis. This review discusses the expression of CC and CXC chemokines in the tumor microenvironment and their supportive and inhibitory roles in tumor progression, angiogenesis, metastasis, and tumor immunity. We also specially focus on the diverse roles of CXC chemokines (CXCL9-11, CXCL4 and its variant CXCL4L1) and their two chemokine receptor CXCR3 isoforms, CXCR3-A and CXCR3-B. These two distinct isoforms have divergent roles in tumors, either promoting (CXCR3-A) or inhibiting (CXCR3-B) tumor progression. Their effects are mediated not only directly in tumor cells but also indirectly via the regulation of angiogenesis and tumor immunity. A full comprehension of their mechanisms of action is critical to further validate these chemokines and their receptors as biomarkers or therapeutic targets in cancer.

Interleukin-2 level for normal people and COVID-19 Infection: is it our concern is COVID-19 Infection or Inreleukin-2 level before the infection?

The newly discovered Coronavirus severe acute respiratory distress syndrome virus-19 (SARAS-COV-2, COVID-19) has become a pandemic issue across the globe. Until now, many investigations are taking place to look for specific, safe, and potent anti-viral agents. Upon transmission and entry into the human body, SARS-COV-2 Trigger multiple external players to be involved in the protection against the viral infection. These include Masks, Gloves, Sanitizing and social distancing. On the other hand, multiple internal body players to be involved in the protection against the viral infection. These include Angiotensin converting enzyme inhibitors or (ACEI) or Angiotensin receptor blockers or (ARB). Also, immune players to be involved in the fight against the viral infection. These include Vaccines, plasma from the Recovered patients and cellular immune players such as B, T and natural killer (NK) Cells, as well as the soluble Cytokines and Chemokines. In this review, we will propose the best way to protect ourselves against COVID-19 infection using Interleukin-2, based on evidences we have. Keywords: COVID-19, drugs, Helper-T cells, Interleukin 2, experimental autoimmune encephalomyelitis, Treg cells and natural killer cells.

IL-36 Signaling in the Tumor Microenvironment.

The ability of the immune system to prevent or control the growth of tumor cells is critically dependent on inflammatory processes that lead to the activation, expansion, and recruitment of antitumor effector cells into the tumor microenvironment (TME). These processes are orchestrated by soluble cytokines produced in tissues that alarm local immune surveillance cells (such as dendritic cells, DCs) to mobilize protective antitumor immune populations (B cells, T cells). The interleukin (IL)-36 family of pro-inflammatory cytokines plays an importantrole in multiple disease processes, ranging from an instigator of autoimmune psoriasis to an initiator of therapeutic immune responses against tumor cells. This chapter will focus on the biologic role of immunomodulatory IL-36 family cytokines in the cancer setting and their potential utility in the design of effective interventional therapies. (127 words).

Activation of IL-10+ B cells: A novel immunomodulatory mechanism for therapeutic bacterial suspensions.

Objectives:Bacterial components are used to improve immune responses in patients with respiratory infections. Pharmacological formulations of bacterial components include a mixture of bacterial antigens, some of which are complete inactivated bacteria, that is, named bacterial suspensions; while others are fragments of bacteria, which are presented as bacterial lysates. Although bacterial lysates have been broadly used as immune-stimulators, the biological support for the therapeutic effectiveness of bacterial suspension has not yet been studied. Thus, the aim of our study was to investigate the immunological activity induced by bacterial suspension.Methods:This work was an exploratory translational study. Peripheral blood mononuclear cells were obtained from healthy donors and cultured in time–dose dependent assays with a commercial bacterial suspension. Flow cytometry was used for phenotypic analysis and for determining soluble cytokines in culture supernatants.Results:We observed that bacterial suspension activates B cells in a dose-dependent manner. Peripheral blood mononuclear cells were able to secrete IL-6 and IL-10 after 24 h of bacterial suspension stimulation. TLR2 expression was observed mainly on CD19+ CD38Lo B cells after 72 h of culture; remarkably, most of the TLR2+ CD19+ cells were also IL-10+.Conclusion:Our findings suggest that bacterial suspension induces the activation of B cell subsets as well as the secretion of IL-6 and IL-10. Expression of TLR2 on CD19+ cells could act as an activation loop of IL-10+ B regulatory cells. The clinical implications of these findings are discussed at the end of this article.

Effects of myeloid and plasmacytoid dendritic cells on ILC2s in patients with allergic rhinitis

Group 2 innate lymphoid cells (ILC2s) were reported to serve a critical role in allergic diseases. Myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) play significant roles in allergic immune response. However, effects of DCs on ILC2s in allergic diseases, especially for patients with allergic rhinitis (AR), remain unclear. We sought to address the roles of mDCs and pDCs in regulating ILC2 function in AR. mDCs and pDCs were cocultured with human PBMCs isolated from patients with AR or ILC2s to measure soluble or intracellular TH2 cytokines, transcription factors, signaling pathways in ILC2s, and the following mechanisms were further investigated. The levels of peripheral IL-33+mDCs, pDCs, and ILC2s were studied in patients under an inhaled allergen challenge. We confirmed the presence of ILC2s, mDCs, and pDCs in the nasal mucosa of patients with AR. Both allogenic and autologous mDCs were found to activate ILC2s from patients with AR to produce TH2 cytokines, and increase the levels of GATA-3 and signal transducer and activator of transcription signaling pathways, in which IL-33-producing mDCs exerted the major role by binding on ST2 on ILC2s. We further identified high levels of IL-33+mDCs and ILC2s in patients with AR under antigen challenge. Activated pDCs inhibited the cytokine production of ILC2s isolated from patients with AR by secretion of IL-6. mDCs promote ILC2 function by the IL-33/ST2 pathway, and activation of pDCs suppresses ILC2 function through IL-6 in patients with AR. Our findings provide new understanding of the interplay between DCs and ILC2s in allergic diseases.