Monoclonal antibodies for equine IL-1ß enable the quantification of mature IL-1ß in horses.

Interleukin-1ß (IL-1ß) is one of the key mediators of inflammation during innate immune responses. Mature bioactive IL-1ß mediates essential host defense mechanisms but also has a mechanistic role in several autoinflammatory and degenerative diseases. In horses, specific and sensitive assays for IL-1ß are crucial for immunological research on inflammatory processes and diseases. In this article, we describe the development of four monoclonal antibodies (mAbs) against equine IL-1ß. The specificity of the new IL-1ß mAbs was confirmed using a panel of equine recombinant cytokines and chemokines. The mAbs were validated for detection of native mature IL-1ß in a fluorescent bead-based assay and for staining of IL-1ß-producing immune cells by flow cytometry. The bead-based assay for equine IL-1ß had a linear quantification range between 60 pg/ml to 960 ng/ml. Horse peripheral blood mononuclear cells (PBMC) secreted IL-1ß after lipopolysaccharide (LPS) stimulation in time and dose dependent manner as quantified by the new equine IL-1ß bead-based assay. A comparison of two commercial equine IL-1ß ELISA kits with the new IL-1ß fluorescent bead-based assay revealed that the bead-based assay improved the quantification of native equine IL-1ß in LPS stimulated PBMC supernatants by detecting it with high intensity and a broad linear quantification range, while both ELISAs resulted in low signals and poor native IL-1ß recognition. Intracellular staining and flow cytometric analysis confirmed that the main cellular source of IL-1ß in equine PBMC after LPS stimulation were CD14+ monocytes. IL-1ß secretion from PBMC was inhibited by a caspase inhibitor but protein translation within the cells was not, supporting the accumulation of pro-IL-1ß within the cells even when proteolytic cleavage for IL-1ß activation is missing. This confirmed the importance of specific mAbs for analyzing the biologically active, mature IL-1ß in horses.

Amlodipine Ocular Delivery Restores Ferning Patterns and Reduces Intensity of Glycosylated Peak of Carrageenan-Induced Tear Fluid: An In-Silico Flexible Docking with IL-ß1.

BACKGROUND: The tear ferning test can be an easy clinical procedure for the evaluation and characterization of the ocular tear film. OBJECTIVE: The objective of this study was to examine the restoration of tear ferning patterns and reduction of glycosylation peak after amlodipine application in carrageenan-induced conjunctivitis. METHODS: At the rabbit's upper palpebral region, carrageenan was injected for cytokine-mediated conjunctivitis. Ferning pattern and glycosylation of the tear fluid were characterized using various instrumental analyses. The effect of amlodipine was also examined after ocular instillation and flexible docking studies. RESULTS: Optical microscopy showed a disrupted ferning of the tear collected from the inflamed eye. FTIR of the induced tear fluid exhibited peaks within 1000-1200 cm-1, which might be due to the protein glycosylation absent in the normal tear spectrogram. The glycosylation peak reduced significantly in the tear sample collected from the amlodipine-treated group. Corresponding energy dispersive analysis showed the presence of sulphur, indicating protein leakage from the lacrimal gland in the induced group. The disappearance of sulphur from the treated group indicated its remedial effect. The flexible docking studies revealed a stronger binding mode of amlodipine with Interleukin-1ß (IL-1ß). The reduction in the intensity of the glycosylated peak and the restoration offering are probably due to suppression of IL-1ß. CONCLUSION: This study may be helpful in obtaining primary information for drug discovery to be effective against IL-1ß and proving tear fluid as a novel diagnostic biomarker.

NLRP3 Inflammasome Inhibitors for Antiepileptogenic Drug Discovery and Development.

Epilepsy is one of the most prevalent and serious brain disorders and affects over 70 million people globally. Antiseizure medications (ASMs) relieve symptoms and prevent the occurrence of future seizures in epileptic patients but have a limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms of these medications for the development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made, and challenges faced in the development of NLRP3 inhibitors for the treatment of epilepsy.

Diagnostic potential of endothelin-1 in peri-implant diseases: a cross-sectional study.

PURPOSE: This study aimed to evaluate the potential of Endothelin-1 (ET-1), a peptide derived from vascular endothelial cells, as a biomarker for diagnosing peri-implant diseases. METHODS: A cohort of 29 patients with a total of 76 implants was included in this study and subsequently divided into three groups based on peri-implant clinical parameters and radiographic examination: healthy (peri-implant health) (n = 29), mucositis (n = 22), and peri-implantitis (n = 25) groups. The levels of ET-1 (ρg/site) and interleukin (IL)-1ß (ρg/site) in peri-implant sulcus fluid (PISF) samples were determined using enzyme immunoassay. Statistical analyses were conducted using Kruskal-Wallis and Steel-Dwass tests. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to evaluate the diagnostic performance of the biomarkers. RESULTS: ET-1 levels were significantly elevated in the peri-implantitis group compared to those in the healthy group, and were highest in the peri-implant mucositis group. Additionally, IL-1ß levels were significantly higher in the peri-implantitis group than those in the healthy group. ROC curve analysis indicated that ET-1 exhibited superior area under the curve values, sensitivity, and specificity compared to those of IL-1ß. CONCLUSIONS: Our findings suggest that the presence of ET-1 in PISF plays a role in peri-implant diseases. Its significantly increased expression in peri-implant mucositis indicates its potential for enabling earlier and more accurate assessments of peri-implant inflammation when combined with conventional examination methods.

Novel NLRP3 inhibitor INF195: Low doses provide effective protection against myocardial ischemia/reperfusion injury.

BACKGROUND: Several factors contribute to ischemia/reperfusion injury (IRI), including activation of the NLRP3 inflammasome and its byproducts, such as interleukin-1ß (IL-1ß) and caspase-1. However, NLRP3 may paradoxically exhibit cardioprotective properties. This study aimed to assess the protective effects of the novel NLRP3 inhibitor, INF195, both in vitro and ex vivo. METHODS: To investigate the relationship between NLRP3 and myocardial IRI, we synthetized a series of novel NLRP3 inhibitors, and investigated their putative binding mode via docking studies. Through in vitro studies we identified INF195 as optimal for NLRP3 inhibition. We measured infarct-size in isolated mouse hearts subjected to 30-min global ischemia/one-hour reperfusion in the presence of three different doses of INF195 (5, 10, or 20-µM). We analyzed caspase-1 and IL-1ß concentration in cardiac tissue homogenates by ELISA. Statistical significance was determined using one-way ANOVA followed by Tukey's test. RESULTS AND CONCLUSION: INF195 reduces NLRP3-induced pyroptosis in human macrophages. Heart pre-treatment with 5 and 10-µM INF195 significantly reduces both infarct size and IL-1ß levels. Data suggest that intracardiac NLRP3 activation contributes to IRI and that low doses of INF195 exert cardioprotective effects by reducing infarct size. However, at 20-µM, INF195 efficacy declines, leading to a lack of cardioprotection. Research is required to determine if high doses of INF195 have off-target effects or dual roles, potentially eliminating both harmful and cardioprotective functions of NLRP3. Our findings highlight the potential of a new chemical scaffold, amenable to further optimization, to provide NLRP3 inhibition and cardioprotection in the ischemia/reperfusion setting.

Hypoxia-induced activation of HIF-1alpha/IL-1beta axis in microglia promotes glioma progression via NF-κB-mediated upregulation of heparanase expression.

BACKGROUND: Glioma is a common tumor that occurs in the brain and spinal cord. Hypoxia is a crucial feature of the tumor microenvironment. Tumor-associated macrophages/microglia play a crucial role in the advancement of glioma. This study aims to illuminate the detailed mechanisms by which hypoxia regulates microglia and, consequently, influences the progression of glioma. METHODS: The glioma cell viability and proliferation were analyzed by cell counting kit-8 assay and 5-ethynyl-2'-deoxyuridine assay. Wound healing assay and transwell assay were implemented to detect glioma cell migration and invasion, respectively. Enzyme-linked immunosorbent assay was conducted to detect protein levels in cell culture medium. The protein levels in glioma cells and tumor tissues were evaluated using western blot analysis. The histological morphology of tumor tissue was determined by hematoxylin-eosin staining. The protein expression in tumor tissues was determined using immunohistochemistry. Human glioma xenograft in nude mice was employed to test the influence of hypoxic microglia-derived interleukin-1beta (IL-1ß) and heparanase (HPSE) on glioma growth in vivo. RESULTS: Hypoxic HMC3 cells promoted proliferation, migration, and invasion abilities of U251 and U87 cells by secreting IL-1ß, which was upregulated by hypoxia-induced activation of hypoxia inducible factor-1alpha (HIF-1α). Besides, IL-1ß from HMC3 cells promoted glioma progression and caused activation of nuclear factor-κB (NF-κB) and upregulation of HPSE in vivo. We also confirmed that IL-1ß facilitated HPSE expression in U251 and U87 cells by activating NF-κB. Hypoxic HMC3 cells-secreted IL-1ß facilitated the proliferation, migration, and invasion of U251 and U87 cells via NF-κB-mediated upregulation of HPSE expression. Finally, we revealed that silencing HPSE curbed the proliferation and metastasis of glioma in mice. CONCLUSION: Hypoxia-induced activation of HIF-1α/IL-1ß axis in microglia promoted glioma progression via NF-κB-mediated upregulation of HPSE expression.

METTL3 deficiency leads to ovarian insufficiency due to IL-1ß overexpression in theca cells.

Premature ovarian insufficiency (POI) is a clinical syndrome characterised by a decline in ovarian function in women before 40 years of age and is associated with oestradiol deficiency and a complex pathogenesis. However, the aetiology of POI is still unclear and effective preventative and treatment strategies are still lacking. Methyltransferase like 3 (METTL3) is an RNA methyltransferase that is involved in spermatogenesis, oocyte development and maturation, early embryonic development, and embryonic stem cell differentiation and formation, but its role in POI is unknown. In the present study, METTL3 deficiency in follicular theca cells was found to lead to reduced fertility in female mice, with a POI-like phenotype, and METTL3 knockout promoted ovarian inflammation. Further, a reduction in METTL3 in follicular theca cells led to a decrease in the m6A modification of pri-miR-21, which further reduced pri-miR-21 recognition and binding by DGCR8 proteins, leading to a decrease in the synthesis of mature miR-21-5p. Decrease of miR-21-5p promoted the secretion of interleukin-1ß (IL-1ß) from follicular theca cells. Acting in a paracrine manner, IL-1ß inhibited the cAMP-PKA pathway and activated the NF-κB pathway in follicular granulosa cells. This activation increased the levels of reactive oxygen species in granulosa cells, causing disturbances in the intracellular Ca2+ balance and mitochondrial damage. These cellular events ultimately led to granulosa cell apoptosis and a decrease in oestradiol synthesis, resulting in POI development. Collectively, these findings reveal how METTL3 deficiency promotes the expression and secretion of IL-1ß in theca cells, which regulates ovarian functions, and proposes a new theory for the development of POI disease.

Interleukin-1 beta (IL-1ß) as adjuvant enhances the immune effects of Aeromonas veronii inactivated vaccine in largemouth bass (Micropterus salmoides).

Largemouth bass (Micropterus salmoides) has emerged as a significant economic fish species, with a rise in Aeromonas veronii infections in farming. However, research on adjuvants for vaccines against A. veronii in largemouth bass remains scarce. In present study, recombinant largemouth bass IL-1ß (LbIL-1ß) was expressed to explore its adjuvant effect on the A. veronii inactivated vaccine. Following vaccination with recombinant LbIL-1ß (rLbIL-1ß) and the inactivated A. veronii, higher serum SOD levels and lysozyme activities were observed in largemouth bass from inactivated A. veronii + rLbIL-1ß vaccinated group. Furthermore, it was discovered that rLbIL-1ß was able to boost the serum-specific antibody levels induced by the inactivated A. veronii. The qRT-PCR analysis revealed that rLbIL-1ß also enhanced the expression of IgM, CD4, and MHC II in largemouth bass triggered by the inactivated A. veronii. After challenged with live A. veronii, the outcomes demonstrated that the relative percentage survival (RPS) for largemouth bass resulting from the inactivated A. veronii in combination with rLbIL-1ß was 76.67 %, surpassing the RPS of 60 % in the inactivated A. veronii group. Collectively, these findings indicate that rLbIL-1ß enhances the protective effect of the A. veronii inactivated vaccine on largemouth bass, showcasing potential as an adjuvant for further development.

IFNγ at the early stage induced after cryo-thermal therapy maintains CD4+ Th1-prone differentiation, leading to long-term antitumor immunity.

Introduction: Recently, more and more research illustrated the importance of inducing CD4+ T helper type (Th)-1 dominant immunity for the success of tumor immunotherapy. Our prior studies revealed the crucial role of CD4+ Th1 cells in orchestrating systemic and durable antitumor immunity, which contributes to the satisfactory outcomes of the novel cryo-thermal therapy in the B16F10 tumor model. However, the mechanism for maintaining the cryo-thermal therapy-mediated durable CD4+ Th1-dominant response remains uncovered. Additionally, cryo-thermal-induced early-stage CD4+ Th1-dominant T cell response showed a correlation with the favorable prognosis in patients with colorectal cancer liver metastasis (CRCLM). We hypothesized that CD4+ Th1-dominant differentiation induced during the early stage post cryo-thermal therapy would affect the balance of CD4+ subsets at the late phase. Methods: To understand the role of interferon (IFN)-γ, the major effector of Th1 subsets, in maintaining long-term CD4+ Th1-prone polarization, B16F10 melanoma model was established in this study and a monoclonal antibody was used at the early stage post cryo-thermal therapy for interferon (IFN)-γ signaling blockade, and the influence on the phenotypic and functional change of immune cells was evaluated. Results: IFNγ at the early stage after cryo-thermal therapy maintained long-lasting CD4+ Th1-prone immunity by directly controlling Th17, Tfh, and Tregs polarization, leading to the hyperactivation of Myeloid-derived suppressor cells (MDSCs) represented by abundant interleukin (IL)-1ß generation, and thereby further amplifying Th1 response. Discussion: Our finding emphasized the key role of early-phase IFNγ abundance post cryo-thermal therapy, which could be a biomarker for better prognosis after cryo-thermal therapy.

Evaluation of IL-1ß and CRP mRNA expression levels by RT-PCR in postorthodontic treatment patients with temporomandibular joint disorders: a cross-sectional Study.

Aim: Temporomandibular joint disorder (TMD), which affects the masticatory muscles, temporomandibular joint, and surrounding tissues, can manifest as inflammation. This study aims to explore the expression levels of the inflammatory biomarkers, interleukin (IL)-1ß and C-reactive protein (CRP), in TMD patients who have undergone orthodontic treatment. Materials and Methods: Buccal swabs from 105 postorthodontic treatment patients were analyzed using real-time polymerase chain reaction to assess the expression levels of IL-1ß and CRP in each group after messenger ribonucleic acid extraction. Patients were also examined using the Diagnostic Criteria for TMD (DC/TMD) to determine if they met the criteria for a TMD diagnosis. The TMD group was subdivided into three categories based on the DC/TMD. Results: The study included 37 patients who did not develop TMD (group 0) and 68 participants who developed TMD after orthodontic treatment, including 17 with pain-related TMDs (group 1), 29 with intra-articular TMDs (Group 2), and 22 with combined pain-related and intra-articular TMDs (group 3). CRP expression was higher than IL-1ß in groups 1 and 2, and IL-1ß expression was higher than CRP in group 3. The Kruskal-Wallis test showed that IL-1ß and CRP expression levels in groups 1, 2, and 3 were not statistically different. Sex and adult age had considerable effects on the occurrence of TMD in patients after orthodontic treatment. Conclusions: Higher IL-1ß expression was found in postorthodontic treatment patients with more complex TMD. This study strengthens the evidence of inflammation through IL-1ß and CRP expression in individuals with TMD, especially after orthodontic treatment.

Estrogen receptor ß activation alleviates inflammatory bowel disease by suppressing NLRP3-dependent IL-1ß production in macrophages via downregulation of intracellular calcium level.

INTRODUCTION: Although several estrogen receptor ß (ERß) agonists have been reported to alleviate IBD, the pivotal mechanism remains obscure. OBJECTIVES: To examine the effects and mechanisms of ERß activation on cytokine/chemokine networks in colitis mice. METHODS: Dextran sulfate sodium salt (DSS) and trinitro-benzene-sulfonic acid (TNBS) were used to induce mouse colitis model. Multiple molecular biological methods were employed to evaluate the severity of mouse colitis and the level of cytokine and/or chemokine. RESULTS: Bioinformatics analysis, ELISA and immunofluorescence results showed that the targeted cytokines and/or chemokines associated with ERß expression and activation is IL-1ß, and the anti-colitis effect of ERß activation was significantly attenuated by the overexpression of AAV9-IL-1ß. Immunofluorescence analysis indicated that ERß activation led to most evident downregulation of IL-1ß expression in colonic macrophages as compared to monocytes and neutrophils. Given the pivotal roles of NLRP3, NLRC4, and AIM2 inflammasome activation in the production of IL-1ß, we examined the influence of ERß activation on inflammasome activity. ELISA and WB results showed that ERß activation selectively blocked the NLRP3 inflammasome assembly-mediated IL-1ß secretion. The calcium-sensing receptor (CaSR) and calcium signaling play crucial roles in the assembly of the NLRP3 inflammasome. WB and immunofluorescence results showed that ERß activation reduced intracellular CaSR expression and calcium signaling in colonic macrophages. Combination with CaSR overexpression plasmid reversed the suppressive effect of ERß activation on NLRP3 inflammasome assembly, and counteracting the downregulation of IL-1ß secretion. CONCLUSION: Our research uncovers that the anti-colitis effect of ERß activation is accomplished through the reduction of IL-1ß levels in colonic tissue, achieved by specifically decreasing CaSR expression in macrophages to lower intracellular calcium levels and inhibit NLRP3 inflammasome assembly-mediated IL-1ß production.

Red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain through stimulating the expressions of TNF-α and IL-1ß.

Our previous study has identified that glutamate in the red nucleus (RN) facilitates the development of neuropathic pain through metabotropic glutamate receptors (mGluR). Here, we further explored the actions and possible molecular mechanisms of red nucleus mGluR Ⅰ (mGluR1 and mGluR5) in the development of neuropathic pain induced by spared nerve injury (SNI). Our data indicated that both mGluR1 and mGluR5 were constitutively expressed in the RN of normal rats. Two weeks after SNI, the expressions of mGluR1 and mGluR5 were significantly boosted in the RN contralateral to the nerve injury. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN contralateral to the nerve injury at 2 weeks post-SNI significantly ameliorated SNI-induced neuropathic pain. However, unilateral administration of mGluRⅠ agonist DHPG to the RN of normal rats provoked a significant mechanical allodynia, this effect could be blocked by LY367385 or MTEP. Further studies indicated that the expressions of TNF-α and IL-1ß in the RN were also elevated at 2 weeks post-SNI. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN at 2 weeks post-SNI significantly inhibited the elevations of TNF-α and IL-1ß. However, administration of mGluR Ⅰ agonist DHPG to the RN of normal rats significantly enhanced the expressions of TNF-α and IL-1ß, these effects were blocked by LY367385 or MTEP. These results suggest that activation of red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain by stimulating the expressions of TNF-α and IL-1ß. mGluR Ⅰ maybe potential targets for drug development and clinical treatment of neuropathic pain.

Vitamin B6 alleviates osteoarthritis by suppressing inflammation and apoptosis.

BACKGROUND: Although various anti-inflammatory medicines are widely recommended for osteoarthritis (OA) treatment, no significantly clinical effect has been observed. This study aims to examine the effects of vitamin B6, a component that has been reported to be capable of alleviating inflammation and cell death in various diseases, on cartilage degeneration in OA. METHODS: Collagen-induced arthritis (CIA) mice model were established and the severity of OA in cartilage was determined using the Osteoarthritis Research Society International (OARSI) scoring system. The mRNA and protein levels of indicators associated with extracellular matrix (ECM) metabolism, apoptosis and inflammation were detected. The effect of vitamin B6 (VB6) on the mice were assessed using HE staining and masson staining. The apoptosis rate of cells was assessed using TdT-mediated dUTP nick end labeling. RESULTS: Our results showed a trend of improved OARSI score in mice treated with VB6, which remarkably inhibited the hyaline cartilage thickness, chondrocyte disordering, and knees hypertrophy. Moreover, the VB6 supplementation reduced the protein expression of pro-apoptosis indicators, including Bax and cleaved caspase-3 and raised the expression level of anti-apoptosis marker Bcl-2. Importantly, VB6 improved ECM metabolism in both in vivo and in vitro experiments. CONCLUSIONS: This study demonstrated that VB6 alleviates OA through regulating ECM metabolism, inflammation and apoptosis in chondrocytes and CIA mice. The findings in this study provide a theoretical basis for targeted therapy of OA, and further lay the theoretical foundation for studies of mechanisms of VB6 in treating OA.

A recombinant IL-1ß vaccine attenuates bleomycin-induced pulmonary fibrosis in mice.

Interleukin-1ß (IL-1ß) contributes to interstitial lung disease (ILD) and pulmonary fibrosis (PF), thus representing a potential therapeutic target for PF. In this study, we first verified the increased expression of IL-1ß in human fibrotic lung specimens and mouse lung tissues after intratracheal (i.t.) instillation of bleomycin (BLM), after which the pro-inflammatory and pro-fibrotic effects of recombinant IL-1ß were tested in mice. The results above suggested that vaccination against IL-1ß could be an effective strategy for managing PF. An anti-IL-1ß vaccine (PfTrx-IL-1ß) was designed by incorporating two IL-1ß-derived polypeptides, which have been verified as the key domains that mediate the binding of IL-1ß to its type I receptor, into Pyrococcus furiosus thioredoxin (PfTrx). The fusion protein PfTrx-IL-1ß was prepared by using E. coli expression system. The vaccine was well tolerated; it induced robust and long-lasting antibody responses in mice and neutralized the biological activity of IL-1ß, as shown in cellular assays. Pre-immunization with PfTrx-IL-1ß effectively protected mice from BLM-induced lung injury, inflammation, and fibrosis. In vitro experiments further showed that anti-PfTrx-IL-1ß antibodies counteracted the effects of IL-1ß concerning pro-inflammatory and pro-fibrotic cytokine production by primary mouse lung fibroblast, macrophages (RAW264.7), and type II alveolar epithelial cell (A549), primary mouse lung fibroblast activation and epithelial-mesenchymal transition (EMT) of alveolar epithelial cells. In addition, the vaccination did not compromise the anti-infection immunity in mice, as validated by a sepsis model. Our preliminary study suggests that the anti-IL-1ß vaccine we prepared has the potential to be developed as a therapeutic measure for PF. Further experiments are warranted to evaluate whether IL-1ß vaccination has the capacity of inhibiting chronic progressive PF and reversing established PF.

Anakinra for Refractory Pseudogout in Patients with End-stage Renal Disease on Haemodialysis.

Calcium pyrophosphate deposition (CPPD) arthritis is the second most common type of crystal-induced arthritis after gout. Acute flares are commonly treated with non-steroidal anti-inflammatory drugs, intra-articular or short-term systemic glucocorticoids or colchicine. However, since there is no pharmacological treatment to reduce CPPD crystal burden, relapsing or chronic CPPD arthritis may be challenging to treat, particularly in patients with end-stage renal disease who are at risk for toxicity of the above medications. Since IL-1ß appears to be driving CPPD arthritis, we treated two patients with chronic CPPD arthritis and end-stage renal disease on haemodialysis with the IL-1ß receptor antagonist anakinra. In both patients, arthritis resolved quickly, while continuation of anakinra maintained remission and allowed complete glucocorticoid withdrawal. Therefore, anakinra may be a safe and effective option both for short and long-term treatment of CPPD arthritis in patients on chronic renal replacement therapy.

Interleukin-1ß: Friend or foe for gastrointestinal cancers.

Gastrointestinal (GI) cancer is a malignancy arising in the digestive system and accounts for approximately a third of increasing global cancer-related mortality, especially in the colorectum, esophagus, stomach, and liver. Interleukin-1ß (IL-1ß) is a leukocytic pyrogen recognized as a tumor progression-related cytokine. IL-1ß secretion and maturation in inflammatory responses could be regulated by nuclear factor-kappaB-dependent expression of NLR family pyrin domain containing 3, inflammasome formation, and activation of IL-1 converting enzyme. Several studies have documented the pro-tumorigenic effects of IL-1ß in tumor microenvironments, promoting proliferation and metastatic potential of cancer cells in vitro and tumorigenesis in vivo. The application of IL-1ß inhibitors is also promising for targeted therapy development in some cancer types. However, as a leukocytic pro-inflammatory cytokine, IL-1ß may also possess anti-tumorigenic effects and be type-specific in different cancers. This editorial discusses the up-to-date roles of IL-1ß in GI cancers, including underlying mechanisms and downstream signaling pathways. Understanding and clarifying the roles of IL-1ß would significantly benefit future therapeutic targeting and help improve therapeutic outcomes in patients suffering from GI cancer.

Neutralization of Interleukin 1-beta is associated with preservation of thalamic capillaries after experimental traumatic brain injury.

Introduction: Traumatic brain injury to thalamo-cortical pathways is associated with posttraumatic morbidity. Diffuse mechanical forces to white matter tracts and deep grey matter regions induce an inflammatory response and vascular damage resulting in progressive neurodegeneration. Pro-inflammatory cytokines, including interleukin-1ß (IL-1ß), may contribute to the link between inflammation and the injured capillary network after TBI. This study investigates whether IL-1ß is a key contributor to capillary alterations and changes in pericyte coverage in the thalamus and cortex after TBI. Methods: Animals were subjected to central fluid percussion injury (cFPI), a model of TBI causing widespread axonal and vascular pathology, or sham injury and randomized to receive a neutralizing anti-IL-1ß or a control, anti-cyclosporin A antibody, at 30 min post-injury. Capillary length and pericyte coverage of cortex and thalamus were analyzed by immunohistochemistry at 2- and 7-days post-injury. Results and Conclusion: Our results show that early post-injury attenuation of IL-1ß dependent inflammatory signaling prevents capillary damage by increasing pericyte coverage in the thalamus.

Secreted Metabolites from Pseudomonas, Staphylococcus, and Borrelia Biofilm: Modulation of Immunogenicity by a Nutraceutical Enzyme and Botanical Blend.

Bacterial biofilms are hardy, adaptable colonies, evading immune recognition while triggering and sustaining inflammation. The goals for this study were to present a method for testing the immunogenicity of secreted metabolites from pathogenic biofilm and to document whether biofilm treated with a nutraceutical enzyme and botanical blend (NEBB) showed evidence of reprogrammed bacterial metabolism, potentially becoming more recognizable to the immune system. We screened immune-modulating properties of metabolites from established biofilm from Pseudomonas aeruginosa (Pa), Stapholycoccus simulans (Ss), and Borrelia burgdorferi (Bb). Secreted metabolites significantly increased the cytokine production by human peripheral blood mononuclear cells, including Interleukin-1-beta (IL-1ß), Interleukin-6 (IL-6), macrophage inflammatory protein-1-alpha (MIP-1α), tumor necrosis factor-alpha (TNF-α), interleukin-1 receptor antagonist (IL-1ra), and interleukin-10 (IL-10). Pa metabolites triggered the most robust increase in IL-1ß, whereas Bb metabolites triggered the most robust increase in IL-10. NEBB-disrupted biofilm produced metabolites triggering altered immune modulation compared to metabolites from untreated biofilm. Metabolites from NEBB-disrupted biofilm triggered increased MIP-1α levels and reduced IL-10 levels, suggesting a reduced ability to suppress the recruitment of phagocytes compared to untreated biofilm. The results suggest that nutraceutical biofilm disruption offers strategies for inflammation management in chronic infectious illnesses. Further clinical studies are warranted to evaluate clinical correlations in infected human hosts.

Interleukin-1ß moderates the relationships between middle frontal-mACC/insular connectivity and depressive symptoms in bipolar II depression.

The functional alterations of the brain in bipolar II depression (BDII-D) and their clinical and inflammatory associations are understudied. We aim to investigate the functional brain alterations in BDII-D and their relationships with inflammation, childhood adversity, and psychiatric symptoms, and to examine the moderating effects among these factors. Using z-normalized amplitude of low-frequency fluctuation (zALFF), we assessed the whole-brain resting-state functional activity between 147 BDII-D individuals and 150 healthy controls (HCs). Differential ALFF regions were selected as seeds for functional connectivity analysis to observe brain connectivity alterations resulting from abnormal regional activity. Four inflammatory cytokines including interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) and five clinical scales including Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), Positive and Negative Syndrome Scale (PANSS), Columbia-Suicide Severity Rating Scale (C-SSRS), and Childhood Trauma Questionnaire (CTQ) were tested and assessed in BDII-D. Partial correlations with multiple comparison corrections identified relationships between brain function and inflammation, childhood adversity, and psychiatric symptoms. Moderation analysis was conducted based on correlation results and previous findings. Compared to HCs, BDII-D individuals displayed significantly lower zALFF in the superior and middle frontal gyri (SFG and MFG) and insula, but higher zALFF in the occipital-temporal area. Only the MFG and insula-related connectivity exhibited significant differences between groups. Within BDII-D, lower right insula zALFF value correlated with higher IL-6, CRP, and emotional adversity scores, while lower right MFG zALFF was related to higher CRP and physical abuse scores. Higher right MFG-mid-anterior cingulate cortex (mACC) connectivity was associated with higher IL-1ß. Moreover, IL-1ß moderated associations between higher right MFG-mACC/insula connectivity and greater depressive symptoms. This study reveals that abnormal functional alterations in the right MFG and right insula were associated with elevated inflammation, childhood adversity, and depressive symptoms in BDII-D. IL-1ß may moderate the relationship between MFG-related connectivity and depressive symptoms.