Inhibition Of IL-33 Research Articles

Population pharmacokinetic/target engagement modelling of tozorakimab in healthy volunteers and patients with chronic obstructive pulmonary disease.

This study describes the pharmacokinetic (PK)/target engagement (TE) relationship of tozorakimab, an anti-interleukin (IL)-33 antibody, by building a mechanistic population PK/TE model using phase 1 biomarker data. The analysis included tozorakimab PK and TE in serum assessed in 60 tozorakimab-treated participants, including healthy adults and patients with mild chronic obstructive pulmonary disease. Scenarios evaluated three dose frequencies (once every 2, 4 or 6weeks) administered subcutaneously at seven doses of tozorakimab (30, 60, 90, 120, 150, 300 or 600 mg). For each dose, simulations were performed with 5000 virtual individuals to predict systemic TE. Inhibition of IL-33/soluble ST2 (sST2) complex levels at trough PK at steady state was assessed in each dosing scenario. The PK/TE modelling analyses were performed using a nonlinear mixed-effect modelling approach. The final two-compartment PK model with tozorakimab binding IL-33 in the central compartment adequately described the systemic PK and TE of tozorakimab at population and individual levels. The mean PK parameter estimates of absorption rate, central volume of distribution and clearance were 0.48 (90% confidence interval [CI]: 0.40-0.59, 1/day), 12.64 (90% CI: 8.60-18.62, L) and 0.87 (90% CI: 0.65-1.16, L/day), respectively. Consistent with the observed value, tozorakimab bioavailability was 45%. For all three dose frequencies, predicted inhibition of systemic IL-33/sST2 levels was more than 95% at doses greater than 90 mg. The PK/TE model reliably quantified the relationship between PK and systemic TE of tozorakimab, with potential utility for predicting clinical dose-response relationships and supporting clinical dose selection.

Epidermal growth factor receptor/mitogen-activated kinase inhibitor treatment induces a distinct inflammatory hair follicle response that includes collapse of immune privilege.

Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated kinase (MEKi) induce a folliculitis in 75-90% of patients, the pathobiology of which remains insufficiently understood. To characterize changes in the skin immune status and global transcriptional profile of patients treated with EGFRi; to investigate whether EGFRi affects the hair follicle's (HF) immune privilege (IP); and to identify early proinflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo. Scalp biopsies were taken from patients exhibiting folliculitis treated long term with EGFRi ('chronic EGFRi' group, n = 9) vs. healthy scalp skin (n = 9) and patients prior to commencing EGFRi treatment and after 2 weeks of EGFRi therapy ('acute EGFRi' group, n = 5). Healthy organ-cultured scalp HFs were exposed to an EGFRi (erlotinib, n = 5) or a MEKi (cobimetinib, n = 5). Samples were assessed by quantitative immunohistomorphometry, RNA sequencing (RNAseq) and in situ hybridization. The 'chronic EGFRi' group showed CD8+ T-cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated major histocompatibility complex (MHC) class I, β2-microglobulin (B2 M) and MHC class II, and decreased transforming growth factor-β1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of human leucocyte antigen (HLA)-A, HLA-DR and B2 M transcripts. RNAseq analysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and interleukin (IL)-26 in biopsies from the 'chronic EGFRi' cohort, as well as increased IL-33 and decreased IL-37 expression in HF biopsies from the 'acute EGFRi' group and in organ-cultured HFs. The data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33.

Endoplasmic reticulum stress drives macrophages to produce IL-33 to favor Th2 polarization in the airways.

Interleukin (IL)-33 is a key driver of T helper 2 (Th2) cell polarization. Endoplasmic reticulum (ER) stress plays a role in the skewed T cell activation. The objective of this project is to elucidate the role of IL-33 derived from macrophages in inducing Th2 polarization in the airways. In this study, bronchoalveolar lavage fluids (BALF) were collected from patients with asthma and healthy control subjects. Macrophages were isolated from the BALF by flow cytometry cell sorting. An asthmatic mouse model was established using the ovalbumin/alum protocol. The results showed that increased IL33 gene activity and ER stress-related molecules in BALF-derived M2a macrophages was observed in asthmatic patients. Levels of IL33 gene activity in M2a cells were positively correlated with levels of asthma response in asthma patients. Sensitization exacerbated the ER stress in the airway macrophages, which increased the expression of IL-33 in macrophages of airway in sensitized mice. Conditional ablation of Il33 or Perk or Atf4 genes in macrophages prevented induction of airway allergy in mice. In conclusion, asthma airway macrophages express high levels of IL-33 and at high ER stress status. Inhibition of IL-33 or ER stress in macrophages can effectively alleviate experimental asthma.

Chaenomeles sinensis Extract Ameliorates Ovalbumin-Induced Allergic Rhinitis by Inhibiting the IL-33/ST2 Axis and Regulating Epithelial Cell Dysfunction.

Chaenomeles sinensis has traditionally been used as an herbal medicine due to its characteristics that protect against inflammation, hypertension, and mutagenesis. However, the effect of Chaenomeles sinensis extract (CSE) on allergic rhinitis (AR) and its underlying mechanisms have yet to be thoroughly investigated. The current study explored the likely effect of CSE on AR in an ovalbumin (OVA)-induced AR mouse model. To this end, OVA-specific immunoglobulins, nasal symptoms, cytokine production, the infiltration of inflammatory cells, and nasal histopathology were assessed to determine the role of CSE against AR. The supplementation of CSE was found to suppress OVA-specific IgE, while OVA-specific IgG2a was increased in the serum. Further, CSE ameliorated the production of T helper type 2 (Th2) cytokines whereas it increased Th1 cytokine levels in nasal lavage fluid. Moreover, the CSE treatment group exhibited significant inhibition of IL-33/ST2 signaling. Subsequently, CES reversed the OVA-induced enhancement of epithelial permeability and upregulated E-cadherin, thus indicating that CES plays a protective role on epithelial barrier integrity. Altogether, the oral administration of CSE effectively controlled allergic response by restricting the buildup of inflammatory cells, enhancing nasal and lung histopathological traits, and regulating cytokines associated with inflammation. Collectively, the results show that the supplementation of CSE at different doses effectively regulated AR, thus suggesting the therapeutic efficiency of CSE in suppressing airway diseases.

Inhibition of IL-33 signaling ameliorate hepatic fibrosis with decreasing MCP-1 in a mouse model of diabetes and non-alcoholic steatohepatitis; comparison for luseogliflozin, an SGLT2 inhibitor

Non-alcoholic fatty liver disease (NAFLD) is increasing globally, and seeking therapeutic molecule targets is urgent. Several studies have demonstrated that IL-33 plays an important role in the progression of Non-alcoholic steatohepatitis (NASH) with fibrosis and the proliferation of hepatocellular carcinoma (HCC). However, whether the inhibition of IL-33 signaling prevents NAFLD from progressing to NASH and HCC has not been clarified. We investigated the effects of a novel antibody, IL-33RAb, and luseogliflozin, a SGLT2 inhibitor, when administered to a model mouse for NASH and HCC, and their effects were compared to investigate the mechanisms of how IL-33 is involved in the pathogenesis of NASH progression. Compared with the positive control of luseogliflozin, inhibition of IL-33 signaling ameliorated decreasing hepatic fibrosis via decreasingαSMA and MCP-1, and also partially suppressed the progression of the HCC cell line in in vitro experiments. These findings suggest that inhibition of IL-33 possibly prevents progression from NASH to HCC, and their effect may be a newly arrived therapeutic agent.

#5413 FRONTIER-1: A PHASE 2B STUDY OF IL-33 BLOCKADE IN DIABETIC KIDNEY DISEASE

Abstract Background and Aims Several biomarkers of inflammation have been correlated with poor renal outcomes and mortality in DKD. However, an effective, well-tolerated treatment of progressive renal disease driven by inflammation has remained elusive. Inhibition of IL-33 may provide a novel opportunity to address this unmet medical need in high-risk patients. Here, we: 1) show that tozorakimab, a high-affinity IL-33-neutralizing mAb, promotes glomerular health in inflammation; 2) describe the clinical study to test tozorakimab in patients with DKD; 3) present participant baseline characteristics; and 4) evaluate inflammation-associated biomarker in FRONTIER-1 and four external validation cohorts. Method FRONTIER-1 (NCT04170543) is a phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of tozorakimab in patients with DKD; defined as T2DM with an eGFR of 25-75 mL/min/1.73 m2 and a UACR in the range of 100-3,000 mg/g. All participants are expected to receive an ACEi/ARB for > 6 weeks before the treatment period. Approximately 565 patients from multiple countries will be randomized to four dose levels of tozorakimab, or volume-matched placebo dosed subcutaneously every 28 days over a 24-week treatment period. All participants will receive 10 mg dapagliflozin Day 85-168. The primary objective of the study is to evaluate the effect of tozorakimab on albuminuria. Secondary objectives are to assess the safety and tolerability of tozorakimab with and without SGLT2i, evaluate the effect of tozorakimab in combination with ACEi or ARB with and without SGLT2i on albuminuria, and describe the PK and immunogenicity of tozorakimab. Key exploratory objective is to assess baseline and treatment-response for urine and/or circulating biomarkers of inflammation, including hsCRP, IL-33/sIL1RL1, CCL2, and TNFR-1/2. Biomarker response was, furthermore, evaluated in pre-clinical models of DKD, and respective distributions and risk were assessed in four independent DKD cohorts (N > 200). Results Transcriptomic profiling of kidney biopsies from patients with DKD indicated a significant glomerular up-regulation of IL-33. Inhibition of IL-33 signalling reduced glomerular damage and albuminuria in the uninephrectomized db/db mouse model of DKD. This was associated with improved glomerular endothelial health as indicated by decreased cellular inflammation and reduced release of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNFR-1, and CCL2. Hence, FRONTIER-1 was started in 2019. So far, all trial groups are well-balanced and in line with our expectations for this patient population (N = 574). At baseline, > 95% were receiving ACEi/ARBs and approximately 25% were receiving SGLT2i. The mean eGFR was 47.8 ml/min/1,73 m2 (+/- 14.7) and mean UACR was 765 mg/g (+/- 775). The inflammatory state of participants at baseline was assessed in circulation and urine by hsCRP, TNFR-1 and CCL2 (N > 146). Comparison to independent reference cohorts (N > 200) confirmed elevated risk in DKD patients with high urinary TNFR-1 and CCL2 and showed that 6-week treatment of dapagliflozin did not alter these biomarkers significantly. Conclusion Taken together, inhibition of IL-33 may be beneficial in patients with DKD on standard of care, who have elevated biomarkers of inflammation such as TNFR-1 and/or CCL2. This hypothesis is currently being tested in the FRONTIER-1 phase 2b clinical study. To identify the patients most likely to benefit from immunomodulatory treatment with tozorakimab, the study will conduct a retrospective analysis of albuminuria and inflammatory biomarkers. The primary analysis of the study is planned for the second half of 2023.

IL-33 Contributes to the Pathological Changes of Hair Follicles in Psoriasis: A Potential Target for Psoriatic Alopecia.

IL-33 is constitutively expressed in skin tissues. Alopecia, a T cells-driven disorder of the hair follicles (HFs), is a common complication in the development of psoriasis. However, the role of IL-33 in psoriatic alopecia remains uncovered. Here, we investigated the roles of IL-33 in inducing pathological changes of hair follicles in psoriasis. Clinical samples and imiquimod (IMQ)-induced psoriatic mice samples were used to investigate the pathological changes and T-cell infiltration of HFs. By using immunohistochemistry staining, the distribution and expression alteration of IL-33 in HFs were determined. Next, by using IL-33 and ST2 knockout mice, we investigated the role of IL-33/ST2 axis in the pathological changes of HFs in psoriasis. Meanwhile, recombinant IL-33 protein was subcutaneous injected to confirm its effect. Finally, RNA sequencing was used to clarify the genes and signaling pathways that involved in this process. Differentially expressed genes were further verified by RT-PCR in cultured HFs in vitro. We found that the pathological changes of HFs and T cells infiltration in imiquimod-induced psoriatic mice were similar to that in psoriasis patients. The IL-33 positive keratinocytes in the outer root sheath of HFs were increased in both psoriasis patients and psoriatic model mice compared with the controls. By using gene knockout mice, we found that the pathological changes and T cell infiltration were attenuated in IL-33-/- and ST2-/- psoriatic model mice. In addition, subcutaneous injection of recombinant IL-33 exacerbated the pathological changes of HFs and T cell infiltration. RNA sequencing and RT-RCR revealed that IL-33 upregulated the transcription of genes related to keratinocytes proliferation and T lymphocytes chemotaxis. Our study identifies that IL-33 promotes the pathological changes of HFs in psoriasis, which contributes to psoriatic alopecia. Inhibition of IL-33 may be a potential therapeutic approach for psoriatic alopecia.

Critical roles of interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) in pulmonary disorders.

Critical roles of interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) in pulmonary disorders.

MIR-181A-5P Attenuates Ovalbumin-Induced Allergic Inflammation in Nasal Epithelial Cells by Targeting IL-33/P38 MAPK Pathway.

Chronic inflammation of the nasal mucosal tissues plays an important role in the pathogenesis of allergic rhinitis (AR). Aberrantly-expressed micro ribonucleic acid (miRNA) has been found to have strong associations with the inflammatory reactions in allergic diseases; however, its functional significance and molecular mechanism in AR remains unclear. The purpose of this study is to determine the functional role and mechanism of miR-181a-5p in AR. Allergic inflammatory reaction was induced by ovalbumin in human nasal epithelial cell line RPMI2650. The anti-inflammatory effects of miR-181a-5p were evaluated by examining pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α)) in the culture of RPMI-2650 cells stimulated by ovalbumin, using quantitative real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Luciferase assay and gain-of-function assay were used to investigate the association of miR-181a-5p and IL-33/p38 MAPK axis. MiR-181a-5p was significantly downregulated in mucosal tissues of AR patients and in RPMI-2650 cells treated with ovalbumin. The overexpression of miR-181a-5p showed prominent suppression of inflammatory cytokine production in RPMI-2650 cells with the stimulation of ovalbumin. MiR-181a-5p directly targeted, and negatively regulated IL-33 to suppress the activation of p38 MAPK signalling. The results suggest that miR-181a-5p restricted allergic inflammation through inhibition of IL-33/p38 MAPK pathway, indicating miR-181a-5p may play an anti-inflammatory role in AR.

Abstract 2679: Role of TH2 cells in pancreatic cancer progression

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that remains largely incurable. Although the cause for this profound therapeutic resistance is poorly understood, it is however partly blamed on signaling factors present in the tumor microenvironment (TME), which supports the proliferation and survival of neoplastic cells. Apart from being stroma rich, PDAC TME is associated with a distinctive tumor immune infiltrate. Paradoxically, most immunotherapy trials using immune checkpoint inhibitors, either as monotherapy or combination, failed to increase patient survival motivating exploration of new therapeutic strategies. To that end, the cytokine mediated heterotypic interactions between cancer cells and immune cells remain largely unexplored. Here, we explored the role of oncogenic Kras (KrasG12D=Kras*) in pro-tumorigenic signaling interactions between cancer cells and host cells. We found that TH2 cells infiltrate the pancreas in the early stage of the tumorigenesis and secrete type 2 cytokines [interleukin (IL)4 and IL13]. Further, Kras* signaling is involved in establishing this paracrine circuit utilizing type 2 cytokines in the PDAC tumor microenvironment (TME)2. Integrated transcriptomic, chromatin occupancy and metabolomic studies identified cMyc, as a direct target of activated Stat6, and that cMyc drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the Kras*-driven metabolic reprogramming of PDAC. This study and the work of others expanded the role of immune cell derived cytokines in the context of Kras* driven PDAC through its promotion of cancer cell proliferation. Importantly, perturbation of the IL4 and/or IL13 mediated signaling restricts tumor growth and increases survival in a mouse model of PDAC. Notably, PDAC patients with predominantly TH2 (Gata3+) polarized lymphoid cell infiltration show reduced survival compared to tumors with higher TH1 (Tbet+) cells. Finally, the presence of TH2 cells in the PDAC TME might explain the immense immunotherapy resistance observed in PDAC patients and anti-TH2 treatment might sensitize these patients to immune checkpoint inhibitors. Our subsequent preliminary work identified a potent inflammatory cytokine, IL33 which is overexpressed and released by PDAC cells that attract and activate TH2 and other immune cells such as Tregs. Inhibition of IL33 leads to a decrease in the infiltration and activation of TH2 cells and Treg cells, accompanied by significant PDAC tumor regression. Citation Format: Aftab Alam, Maulasri Bhatta, Parker Denz, Eric Levanduski, Prasenjit Dey. Role of TH2 cells in pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2679.

Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection

SummaryHow helminths influence the pathogenesis of sexually transmitted viral infections is not comprehensively understood. Here, we show that an acute helminth infection (Nippostrongylus brasiliensis [Nb]) induced a type 2 immune profile in the female genital tract (FGT). This leads to heightened epithelial ulceration and pathology in subsequent herpes simplex virus (HSV)-2 infection. This was IL-5-dependent but IL-4 receptor alpha (Il4ra) independent, associated with increased FGT eosinophils, raised vaginal IL-33, and enhanced epithelial necrosis. Vaginal eosinophil accumulation was promoted by IL-33 induction following targeted vaginal epithelium damage from a papain challenge. Inhibition of IL-33 protected against Nb-exacerbated HSV-2 pathology. Eosinophil depletion reduced IL-33 release and HSV-2 ulceration in Nb-infected mice. These findings demonstrate that Nb-initiated FGT eosinophil recruitment promotes an eosinophil, IL-33, and IL-5 inflammatory circuit that enhances vaginal epithelial necrosis and pathology following HSV-2 infection. These findings identify a mechanistic framework as to how helminth infections can exacerbate viral-induced vaginal pathology.

Fragility can be a good thing in cancer.

IL-33 is shown to play a cell-intrinsic role in maintenance of the functional identity of regulatory T cells in the tumor microenvironment. Genetic inhibition of IL-33 potentiates the therapeutic effect of checkpoint inhibitor immunotherapy in a melanoma mouse tumor model.

Interleukin-33 signaling contributes to renal fibrosis following ischemia reperfusion

Acute kidney injury caused by ischemia-reperfusion injury (IRI) is a major risk factor for chronic kidney disease, which is characterized by renal interstitial fibrosis. However, the molecular mechanisms underlying renal fibrosis induced by IRI are not fully understood. Our results showed that interleukin (IL)−33 was induced markedly after IRI insult, and the kidneys of mice following IRI plus IL-33 treatment presented more severe renal fibrosis compared with mice treated with IRI alone. Therefore, we investigated whether inhibition of IL-33 protects against IRI-induced renal fibrosis. Mice were administrated with soluble ST2 (sST2), a decoy receptor that neutralizes IL-33 activity, or vehicle by intraperitoneal injection for 14 days after IRI challenge. We revealed that mice treated with sST2 exhibited less severe renal dysfunction and fibrosis in response to IRI compared with vehicle-treated mice. Inhibition of IL-33 suppressed bone marrow–derived fibroblast accumulation and myofibroblast formation in the kidneys after IRI stress, which was associated with less expression of extracellular matrix proteins. Furthermore, inhibition of IL-33 also showed a significant reduction of F4/80+ macrophages and CD3+ T cells in the kidneys of mice after IRI treatment. Finally, Treatment with IL-33 inhibitor reduced proinflammatory cytokine and chemokine levels in the kidneys of mice following IRI insult. Taken together, our findings indicate that IL-33 signaling plays a critical role in the pathogenesis of IRI–induced renal fibrosis through regulating myeloid fibroblast accumulation, inflammation cell infiltration, and the expression of proinflammatory cytokines and chemokines.

Sterile type 2 inflammation triggered by microparticles is abrogated by inhibition of IL33 through blockade of Bruton’s tyrosine kinase

Abstract Wear debris microparticle release associated with total joint arthroplasty may contribute to harmful inflammation, osteolysis and implant failure. We examined the role of different molecular signaling pathways in microparticle-mediated inflammation. Intraperitoneal inoculation of cobalt chrome (CoCr) in mice induced a robust innate type 2 response with increases in IL4, IL5, IL13, IL33, M2 macrophages, eosinophils and neutrophils compared to controls given vehicle only. Blockade of the SYK signaling pathway with the inhibitor BAY 61-3606 or the down stream BTK signaling pathway with Ibrutinib abrogated the CoCr-mediated innate type 2 inflammation. Further studies in CBA/Nxid mice, a genetic BTK loss of function mutant also showed decreases in type 2 inflammation, confirming a critical role for BTK in CoCr mediated sterile type 2 inflammation. Inoculation of JH−/−, B cell deficient mice, or depletion of T cells by anti-CD4 (GK1.5) antibody, had no impact on CoCr mediated type 2 inflammation. We further demonstrated that the major source of IL33 was macrophages and intra-peritoneal administration of recombinant IL33 rescued the CoCr mediated type 2 response after BTK blockade. These studies indicate that the type 2 immune response caused by solid particles is abrogated by blockade of BTK signaling pathways and that exogenous IL33 is sufficient to rescue this response. These studies elucidate the nature of wear debris-mediated type 2 sterile inflammation and provide potential targets for future therapy.

Evaluation of Anti-Inflammatory Activities of Qingre-Qushi Recipe (QRQS) against Atopic Dermatitis: Potential Mechanism of Inhibition of IL-33/ST2 Signal Transduction.

To evaluate the anti-inflammatory activities of QRQS against AD and the inhibitory molecular mechanisms of IL-33/ST2 signal transduction, BALB/c mice were divided into six groups (normal control, OVA control, low-dose of QRQS, middle-dose of QRQS, high-dose of QRQS, and cetirizine) and epicutaneously exposed to ovalbumin or PBS for 3 weeks and treated with QRQS for 2 weeks. Skin biopsies and blood samples were obtained for histological study, antibody analysis, and RNA isolation. HaCaT cells, stimulated by TNF-α and IFN-γ, were treated with QRQS to evaluate mRNA and protein expression by RT-PCR and ELISA. QRQS decreased both epidermal and dermal thickness, alleviated dermatitis, and reduced IL-33 and ST2 positive cell numbers. The concentration of specific IgE, IgG, IgG1, and IgG2a antibodies in serum and the expression of IL-33, ST2, IL-1RAcP, IL-4, and IL-13 mRNA in the skin were suppressed. No significant difference exists in TNF-α or IFN-γ. QRQS decreased IL-33 mRNA and protein secretion in HaCaT cells exposed to TNF-α and IFN-γ in a time- and concentration-dependent manner. QRQS regulates related molecule expression of ovalbumin-induced dermatitis involved in the IL-33/ST2 signaling axis in the treatment of acute AD.

MicroRNA-487b Is a Negative Regulator of Macrophage Activation by Targeting IL-33 Production.

MicroRNAs (miRNAs) are short noncoding RNAs that regulate a broad spectrum of biological processes, including immune responses. Although the contributions of miRNAs to the function of immune cells are beginning to emerge, their specific roles remain largely unknown. IL-33 plays an important role in macrophage activation for innate host defense and proinflammatory responses. In this study, we report that miR-487b can suppress the levels of mRNA and protein for IL-33 during the differentiation of bone marrow-derived macrophages (BMDMs). This results in inhibition of IL-33-induced expression of Ag-presenting and costimulatory molecules and proinflammatory mediators. A luciferase assay showed that miR-487b binds to the IL-33 3'-untranslated region. We also confirmed that IL-33 directly promotes the activation of BMDMs by increasing the expression of MHC class I, MHC class II, CD80/CD86, and inducible NO synthase (iNOS) in a dose-dependent manner. Exposure of BMDMs to the TLR4 ligand, LPS, decreased miR-487b expression, increased IL-33 transcript levels, and induced the production of proinflammatory mediators (e.g., iNOS, IL-1β, IL-6, and TNF-α). Treatment with a specific inhibitor of miR-487b function also resulted in increased levels of IL-33 mRNA, which augmented LPS-induced expression of these inflammatory mediators in macrophages. Collectively, our results indicate that miR-487b plays a negative regulatory role in macrophages by controlling the levels of IL-33 transcript and protein to fine-tune innate immune host defense and proinflammatory responses of these cells. Thus, miR-487b plays an important role in the regulation of macrophage homeostasis and activation by targeting IL-33 transcripts.

Vitamin D enhances production of soluble ST2, inhibiting the action of IL-33

Vitamin D enhances production of soluble ST2, inhibiting the action of IL-33