Specific Proinflammatory Cytokines Research Articles

Inflammatory biomarkers profiles and cognition among older adults

Inflammation plays a major role in cognitive aging. Most studies on peripheral inflammation and cognitive aging focused on selected major inflammatory biomarkers. However, inflammatory markers are regulated and influenced by each other, and it is therefore important to consider a more comprehensive panel of markers to better capture diverse immune pathways and characterize the overall inflammatory profile of individuals. We explored 23 circulating inflammatory biomarkers using data from 1,743 participants without dementia (≥ 65 years-old) from the community-based, multiethnic Washington Heights Inwood Columbia Aging Project. Using principal component analysis (PCA), we developed six inflammatory profiles (PC-1 to PC-6) based on these 23 biomarkers and tested the association of resulting inflammatory profile with cognitive decline, over up to 12 years of follow-up. PC-1 described a pro-inflammatory profile characterized by high positive loadings for pro-inflammatory biomarkers. A higher PC-1 score was associated with lower baseline cognitive performances. No association of this profile with cognitive decline was observed in longitudinal analysis. However, PC-5 characterized by high PDGF-AA and RANTES was associated with a faster cognitive decline. Among older adults, a circulating pro-inflammatory immune profile is associated with lower baseline cognitive performance, and some specific pro-inflammatory cytokines might be associated with faster cognitive decline.

Current Status of Gout Arthritis: Current Approaches to Gout Arthritis Treatment: Nanoparticles Delivery Systems Approach.

The deposition of monosodium urate (MSU) crystals within joint spaces produces a painful inflammatory condition known as gout, a specific form of arthritis. The condition calls for a combined curative and preventive management model. A new development in the approach to gout is that of NLRP3-targeted biologic agents, such as monoclonal therapies, to provide more accurate treatment by blocking specific pro-inflammatory cytokines. Nanoparticle drug delivery enhances biological availability and delivery to targets, which may increase therapeutic efficacy and decrease general toxicity. The preventive approach again cannot be ignored, mainly keeping up certain modifications in diet and weight, along with pharmacological therapies to reduce uric acid (UA) levels and to decrease the frequency of acute attacks. The advancement of genetic profiling of patients and biomarker discoveries drives the trend towards building individualized medicine and care, quickly gaining ground as the most effective method of delivering treatments to individual patients, moving away from one-size-fits-all treatments. The following paper aims to provide an updated account of the management of gout with a focus on recent developments, in order to enhance these approaches, the quality of life for patients with gout, and the standard of gout treatment.

P07 The use of JAK inhibitors in difficult-to-treat adult-onset Still’s disease

Abstract Introduction Adult-onset Still’s Disease (AOSD) is a rare systemic auto-inflammatory disorder characterised by fever, arthritis and rash. Some patients with AOSD exhibit resistance or intolerance to conventional treatments, necessitating alternative therapeutic strategies. This case explores the efficacy and safety of janus kinase (JAK) inhibitors in managing difficult-to-treat AOSD. The driving force behind Still’s disease lies in the excessive and inappropriate production of pro-inflammatory cytokines, notably interleukin-6 (IL-6) and interferon (IFN). Given the pivotal role of JAK inhibitors in mitigating these cytokine pathways, this study highlights their potential therapeutic impact in the management of difficult-to-treat AOSD. Case description A 32-year-old male presented in July 2021 with a three-week history of fevers, night sweats, rigors, and weight loss. A CT scan revealed widespread lymphadenopathy above and below the diaphragm. Blood cultures were negative and, despite antibiotics, the patient continued to experience intermittent fevers. Anemia was asymptomatic, and the patient was transfused with two units of blood. Chronic B infection led to the initiation of entecavir. The patient also experienced palpitations and tachycardia, with an echo revealing a small pericardial effusion, hypertrophied and hyperdynamic left ventricle (LV) with an ejection fraction of 70-75%. A lymph node biopsy was inconclusive, prompting a second biopsy. In September 2021, hyponatremia due to SIADH developed. The patient had ongoing symptoms, including weight loss, and a bone marrow biopsy showed reactive features. CT and PET scans revealed generalised lymphadenopathy. Rheumatology consultation in November 2021 indicated intermittent fever, weight loss, joint pain, and elevated inflammatory markers. The patient had dermatographic lymphadenopathy, and a negative lymph node biopsy lowered the probability of HLH. Methotrexate was initiated, later switched to azathioprine and prednisolone due to ongoing symptoms. In June 2022, the patient started tocilizumab, which resolved joint pain but caused ongoing dermatitis. Tocilizumab was discontinued in January 2023 due to inefficacy, and anakinra was initiated. Prednisolone was gradually tapered off. The patient experienced shortness of breath, and echo revealed pulmonary hypertension. Tocilizumab was discontinued due to injection site reactions and increased hepatitis B virus titers. In March 2023, the decision was made to start the JAK inhibitor tofacitinib. By May 2023, ferritin levels were 1196, and the patient was successfully coming off prednisolone with well-controlled symptoms. Discussion This case underscores the efficacy of JAK inhibitors as a successful therapeutic intervention in challenging cases of AOSD. The 32-year-old male presented with severe symptoms including fevers, night sweats, weight loss, and widespread lymphadenopathy. Initial treatments with antibiotics, methotrexate, azathioprine, prednisolone, and tocilizumab were either ineffective or led to adverse reactions. Despite these setbacks, the patient showed a remarkable clinical response to the JAK inhibitor tofacitinib, initiated in March 2023. The swift and sustained improvement in symptoms, along with a favourable safety profile, suggests that JAK inhibitors can be a promising treatment for refractory AOSD. The ability to taper off steroids while maintaining symptom control is particularly noteworthy, as long-term steroid use is associated with significant side effects. The success of JAK inhibitors in this case is likely attributed to their mechanism of action, which strategically blocks pro-inflammatory cytokine pathways, particularly IL-6 and IFN. This targeted approach addresses the underlying pathophysiology of AOSD, leading to better disease management. However, this case also highlights the importance of monitoring for potential side effects, such as increased hepatitis B virus titres observed in this patient. This necessitated adjustments in therapy and careful monitoring of liver function. The encouraging outcomes in this case prompt the need for further prospective studies to validate these findings. Future research should focus on elucidating the optimal dosing and duration of JAK inhibitor therapy in patients with refractory AOSD. Additionally, long-term follow-up studies are essential to fully understand the safety profile of these agents. Key learning points • Refractory AOSD treatment: JAK inhibitors, such as tofacitinib, can be effective for patients with refractory AOSD who do not respond to conventional therapies. • Steroid sparing: JAK inhibitors may allow for the tapering off of steroids, reducing the risk of long-term steroid-related side effects. • Cytokine pathway targeting: The success of JAK inhibitors highlights the importance of targeting specific pro-inflammatory cytokine pathways, particularly IL-6 and IFN, in managing AOSD. • Monitoring side effects: Continuous monitoring for potential side effects, including increased the risk of thromboembolic events is crucial when using JAK inhibitors. • Need for further research: Prospective studies are needed to validate the efficacy and safety of JAK inhibitors in AOSD and to determine optimal dosing and treatment duration.

Correlation Between Reduced IL-1β Levels in Acne Lesions and the Decrease in Acne Inflammatory Lesions Following Topical Vitamin D Administration: A Double-Blind Randomized Controlled Trial.

The inflammatory process in acne vulgaris (AV) is characterized by the upregulation of specific pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and IL-8, within sebocytes and keratinocytes. Sebocytes have been identified as target cells for bioactive vitamin D. Experimental studies on animal models have demonstrated the potent comedolytic effects of topical vitamin D. However, further research is required to specifically evaluate the impact of vitamin D on inflammatory lesions in acne vulgaris (AV). To evaluate the effectiveness of topical vitamin D in treating acne vulgaris (AV) lesions by investigating its anti-inflammatory effects on pro-inflammatory cytokine modulation, specifically assessing the correlation between IL-1β levels in acne lesions and the reduction in AV severity. This study is a double-blind, randomized, placebo-controlled clinical trial with a 2-arm design over an 8-week intervention period. Participants were randomly assigned to either the topical vitamin D group (cholecalciferol 50 mcg) or the topical placebo group, with each group comprising 32 subjects. All participants received concomitant treatment with topical adapalene 0.1%. Cytokine levels within acne lesions were assessed using Luminex Polystyrene Screening Assays to detect and quantify IL-1β levels. The effectiveness of the treatment was evaluated by monitoring the reduction in the number of inflammatory lesions, while the safety of topical vitamin D was assessed by documenting and analyzing any reported side effects. The study found a significant correlation between the reduction in IL-1β levels within acne lesions and the decrease in moderate and severe inflammatory lesions in acne vulgaris (p = 0.028). The topical application of vitamin D led to a significant reduction in inflammatory AV lesions (p = 0.045). No significant topical side effects were observed in either the vitamin D or placebo groups. This study demonstrates that the topical administration of vitamin D in acne vulgaris (AV) lesions is effective in reducing pro-inflammatory cytokine levels within acne lesions and in decreasing the severity of AV. NCT05758259. September 5, 2022.

Impact of Fresh Khat Extract on Proinflammatory Cytokines and Hepatic and Renal Responses.

BACKGROUND This study examined the effects of khat extract on the proinflammatory cytokines, liver, and kidneys of rats. Unlike previous research that focused on broad immune markers and general effects, this study investigated specific proinflammatory cytokines (IL-1ß, IL-2, IL-4, IL-6, and TNF-alpha) and considered gender differences in the immune response. Fresh khat plants and nontoxic doses were used to obtain clear observations relevant to human health. MATERIAL AND METHODS Extracts were prepared from young shoots of khat plants and fresh leaves. 150-gram male and female rats were randomly divided into 8 groups (5 rats per group). Six groups received the extract orally for 8 weeks at doses of 100, 300, and 500 mg/kg/day. Blood samples were collected after 56 days and assayed for cytokines using ELISA, while liver enzymes and kidney markers were assayed using kinetics and colorimetric methods. RESULTS Khat extract increased the levels of most cytokines, with higher doses causing greater increase. This effect was consistent across sexes for some cytokines (IL-1ß, IL-2), but not others (IL-4, IL-6, TNF-alpha), where sex played a role at specific doses. Various doses of the extract influenced glucose levels in both male and female rats. In addition, liver enzyme markers showed some variations. CONCLUSIONS This study, with its intriguing findings, illuminates the complex effects of khat on various systems. Variations in AST and ALT levels in the liver support earlier hepatotoxicity research and suggest possible khat-induced damage. This study revealed consistently increased levels of all cytokines as the dose of khat extract increased.

Netakimab in the treatment of psoriatic erythroderma

Psoriasis is considered as system immunoassociated disease of the multifactorial nature with dominating value in development of genetic factors. Suffer псориазом from 2 to 7% of inhabitants of a planet. Psoriasis it is started, when environment factors activate plasmocytoid dentrid cages that leads to development numerous proinflammatory citokines, including the factor некроза to a tumour FNO-α, interferon (IFN) γ, interleukin (IL) 17, IL-22, IL-23 and IL-1β. Many of these citokines stimulate hyperproliferation keratinocyes which supports a chronic inflammation. The heaviest form psoriasis – psoriatic erythroderma, results adverse экзогенных from the factors, irritating treatment. Develops erythroderma at 1.5–3% of patients псориазом which amazes all surface of an integument. All skin cover gets brightly red colour, with a brown shade, is strained. Taking into account recent achievements in understanding of the inflammatory nature psoriatic research efforts have been concentrated to finding-out of a role specific proinflammatory cytokines which participate in pathogenesis diseases, for the purpose of working out of new purposeful methods of treatment. For treatment psoriatic erythroderma in medicine there is a wide spectrum of external and system means. Undoubtedly, psoriatic erythroderma has all indications to appointment of biological therapy, especially when does not give in traditional methods. Authors of article have presented a therapy material psoriatic erythroderma, a domestic preparation of genno-engineering biological therapy of (netakimab). The good clinical effect that opens prospect of application of this preparation is gained. The concrete clinical example of successful treatment is resulted.

Adipokine receptor expression in mast cells is altered by specific ligands and proinflammatory cytokines.

Adipokines play essential roles in regulating a range of biological processes, but growing evidence indicates that they are also fundamental in immunological mechanisms and, primarily, inflammatory responses. Adipokines mediate their actions through specific receptors. However, although adipokine receptors are widely distributed in many cell and tissue types, limited data are available on their expression in mast cells (MCs) and, consequently, adipokine's significance in the modulation of MC activity within the tissues. In this study, we demonstrate that rat peritoneal MCs constitutively express the leptin receptor (i.e. LEPR), adiponectin receptors (i.e. ADIPOR1 and ADIPOR2) and the chemerin receptor (i.e. CMKLR1). We also found that LEPR, ADIPOR1, ADIPOR2 and CMKLR1 expression in MCs changes in response to stimulation by their specific ligands and some cytokines with potent proinflammatory properties. Furthermore, the involvement of intracellular signaling molecules in leptin-, adiponectin- and chemerin-induced MC response was analyzed. Overall, our findings suggest that adipokines leptin, adiponectin and chemerin can significantly affect the activity of MCs in various processes, especially during inflammation. These observations may contribute significantly to understanding the relationship between adipokines, immune mechanisms and diseases or conditions with an inflammatory component.

Elevated Specific Pro-Inflammatory Cytokines in Peripheral Circulation Indicate an Increased Risk of Anxiety and Depression in Rosacea.

Pro-inflammatory cytokines mediate the course of rosacea, anxiety, and depression through various means such as immunity and inflammation. This study aims to further explore the relationship between rosacea, anxiety, and depression through changes in the levels of pro-inflammatory cytokines. 280 rosacea patients were included in the rosacea group, divided into: rosacea without mental disorders, rosacea with anxiety, rosacea with depression, and rosacea with combined anxiety and depression. The mental control group included 210 anxiety and depression patients, divided into: anxiety, depression, and combined anxiety and depression. The healthy control group consisted of 70 healthy individuals. Serum specimens were collected and ELISA was used to detect major pro-inflammatory cytokines. CEA, IGA, GFSS, RosaQoL, HAMA, and HAMD-24 were used for the diagnosis and severity assessment of rosacea and anxiety and depression. This study primarily used the Chi-Square test, Kruskal-Wallis H-test, generalized linear model, and binary logistic regression to evaluate the data. IL-1β, IL-17, and IL-8 levels in rosacea patients and anxiety/depression patients were higher than those in the healthy population (P<0.001), and TNF-α levels in rosacea patients were higher than those in the healthy population (P<0.001). There was an interaction between rosacea, anxiety, and depression in terms of IL-1β, IL-17, and IL-8 levels (P<0.001). Elevated levels of IL-1β, IL-17, and IL-8 are positively correlated with anxiety and depression in rosacea (all P<=0.05). It was confirmed that the elevated levels of IL-1β, IL-17, and IL-8 are positively correlated with the onset of anxiety and depression in rosacea. The interaction of the above inflammatory factors suggests a possible common inflammatory mechanism in the coexistence of rosacea and mental disorders. TNF-α only increased in patients with rosacea, combined with the skin-to-mental irreversible phenomenon, indicating that this cytokine may be a key and potential therapeutic target for the onset of rosacea.

Circadian Variation of Immune Cell Populations in Preterm Human Milk: A Preliminary Study.

Introduction: Breast milk contains both nutritional and non-nutritional components for the newborn, with some of the latter exhibiting marked diurnal variations in concentration. This study aimed to analyze the circadian behavior of specific immune cell populations and proinflammatory cytokines present in the transitional milk of premature infants. Methods: The study quantified cellular components, including stem and immune cells, using flow cytometry. Additionally, ELISA assays were employed to measure proinflammatory cytokine concentrations. Results: Flow cytometry analyses revealed a diurnal rise in the percentage of CD23+, CD32+, CD36+, CD2+, and Tγδ cell populations. Conversely, nocturnal increases were observed in the percentage of CD16+, CD19+, and CD4+ populations. Notably, CD3+ and CD8+ populations did not exhibit any rhythmic variations. Proinflammatory cytokine concentrations were found to be higher in daytime milk samples compared to those collected at night. Conclusion: This study demonstrates rhythmic fluctuations in both immune cell populations and proinflammatory cytokine concentrations within the transitional milk of premature mothers.

New pyrazole-pyridazine hybrids as selective COX-2 inhibitors: design, synthesis, molecular docking, in silico studies and investigation of their anti-inflammatory potential by evaluation of TNF-α, IL-6, PGE-2 and NO in LPS-induced RAW264.7 macrophages.

Hybrid-based design has gained significant interest in the development of novel active substances with anti-inflammatory properties. In this study, two series of new pyrazole-pyridazine-based hybrids, 5a-f and 6a-f, were designed and synthesized. Molecules containing pyrazole and pyridazine pharmacophores in a single molecule, each with a unique mechanism of action and different pharmacological characteristics, are believed to exert higher biological activity. The cell viability of all compounds was evaluated using MTT assay in LPS-induced RAW264.7 macrophages. In vitro COX-1 and COX-2 inhibition assays were performed for the investigation of the anti-inflammatory activity of target compounds. Trimethoxy derivatives 5f and 6f were the most active candidates, demonstrating higher COX-2 inhibitory action than celecoxib, with IC50 values of 1.50 and 1.15 μM, respectively. Bromo derivative 6e demonstrated a COX-2 inhibitory activity comparable to celecoxib. Further, the ability of compounds 5f, 6e, and 6f to inhibit the generation of specific pro-inflammatory cytokines and mediators, including nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and prostaglandin-E2 (PGE-2), in RAW264.7 macrophages stimulated by LPS was also estimated. Compounds 5f and 6f demonstrated the most potent activity. Morover, according to the investigation using molecular modeling studies, derivatives 5f and 6f showed respectable binding affinity towards the COX-2 active site compared to the reference ligand. Moreover, the ADME parameters, physicochemical characteristics, pharmacokinetic characteristics, and l of the most potent compounds were also computed.

Role of Infrapatellar Fat Tissue in the Pathogenesis of Knee Osteoarthritis: A Review

Osteoarthritis (OA) is one of the most common joint diseases in the adult population. The role of indolent inflammation and predominance of catabolic cytokines over anabolic ones in OA has now been proven. The influence of obesity on the development of OA by releasing inflammatory mediators by fat tissue has been confirmed. Infrapatellar fat tissue (Hoffa’s fat pad) is a potential donor of proinflammatory cytokines, including specific fat tissue proinflammatory cytokines - adipokines. In a healthy person, infrapatellar fat tissue contributes to the distribution of mechanical load on the joint and metabolism of the synovial fluid. Infiltration of infrapatellar fat tissue by macrophages and lymphocytes leads not only to the production of proinflammatory cytokines with chondrolytic properties, but also to the maintenance of chronic inflammation in the synovial membrane, articular cartilage, and subchondral bone. Morphologic changes in Hoffa’s fat pad can be both an indicator of the inflammatory process in the joint cavity and a predictor of pathologic changes of the joint. Among histological changes, infiltration with macrophages and lymphocytes, fibrosis, thickening of the interlobular septa, reduction in the size of fat lobules and adipocytes, and increased vascularization are important for the course of OA. Morphologic changes can be assessed using a non-invasive method - magnetic resonance imaging, which makes it possible to evaluate the presence and severity of synovitis, thickening of the synovial membrane, edema, thickening of the interlobular septa, and a decrease in the volume of Hoffa’s fat pad. Histologic and tomographic signs can potentially be used to assess the severity of OA and develop prognostic scales. Infrapatellar fat tissue is also a source of mesenchymal stem cells phenotypically similar to chondrocytes, which can be used for regeneration of joint cartilage tissue with minimally invasive intervention to harvest them.

The influence of dietary sugar intake on colorectal cancer

Research Question: This study aims to investigate the consequences of daily sugar intake on human health, particularly focusing on its role in the development of colorectal cancer. The research question explores the intricate mechanisms linking elevated sugar consumption to colorectal cancer and aims to understand the diverse dietary regimens influence on this association. Methods: A comprehensive analysis was conducted to examine the impact of persistent, elevated sugar consumption on the integrity of the intestinal tract and its correlation with colorectal cancer. Various dietary regimens, characterized by different sugar types and quantities, were studied to understand their role in exacerbating the likelihood of developing colorectal cancer. Detailed investigations were carried out to unravel the underlying mechanisms, including insulin resistance, systemic cellular inflammatory responses, and the shift in colonic biological milieu. Inflammatory mediators and specific pro-inflammatory cytokines were analysed in different tissue compartments to comprehend the complex interplay leading to compromised intestinal barrier integrity and increased susceptibility to colorectal cancer. Conclusion: Our study reveals compelling evidence linking high-sugar diets to the development of colorectal cancer. Elevated sugar consumption disrupts the integrity of the intestinal tract, primarily through insulin resistance and systemic cellular inflammatory responses. This disruption leads to an upsurge in inflammatory mediators and specific pro-inflammatory cytokines within various tissue compartments. Consequently, the compromised intestinal barrier loses its ability to prevent the infiltration of pathogenic microorganisms, significantly elevating the risk of colorectal cancer. The diverse range of dietary regimens further complicates this association, highlighting the need for comprehensive research in understanding the intricate role of dietary factors in colorectal cancer.

Treatment cessation in HBeAg-negative chronic hepatitis B: clinical response is associated with increase in specific proinflammatory cytokines

Patients with HBeAg-negative chronic hepatitis B may experience an immune response after stopping nucleos(t)ide analogue (NA)therapy, which may potentially trigger HBsAg loss or off-therapy sustained viral control. The immunological mechanisms determining clinical response remain poorly understood. To identify inflammatory signatures associated with defined outcomes, we analysed plasma cytokines and chemokines from 57 HBeAg-negative patients enrolled in the Nuc-Stop Study at baseline and 12 weeks after NA cessation. Clinical response at 12 weeks was classified into four groups: immune control, viral relapse, evolving clinical relapse, and resolving clinical relapse. Twelve weeks after treatment cessation 17 patients (30%) experienced immune control, 19 (33%) viral relapse, 6 (11%) evolving clinical relapse, and 15 (26%) resolving clinical relapse. There was a significant increase in interferon-γ-induced protein 10 (IP-10; p = 0.012) and tumor necrosis factor (TNF; p = 0.032) in patients with evolving clinical relapse. Sparse partial least-squares multivariate analyses (sPLS-DA) showed higher first component values for the clinical relapse group compared to the other groups, separation was driven mainly by IP-10, TNF, IL-9, IFN-γ, MIP-1β, and IL-12. Our results demonstrate that evolving clinical relapse after NA cessation is associated with a systemic increase in the proinflammatory cytokines IP-10 and TNF.Clinical trial registration: ClinicalTrials.gov, Identifier: NCT03681132.

Prolactin inhibits or stimulates the inflammatory response of joint tissues in a cytokine-dependent manner.

The close association between rheumatoid arthritis (RA), sex, reproductive state, and stress has long linked prolactin (PRL) to disease progression. PRL has both proinflammatory and anti-inflammatory outcomes in RA, but responsible mechanisms are not understood. Here, we show that PRL modifies in an opposite manner the proinflammatory actions of IL-1β and TNF-α in mouse synovial fibroblasts (SF) in culture. Both IL-1β and TNF-α upregulated the metabolic activity and the expression of proinflammatory factors (Il1b, Inos, and Il6) via the activation of the NF-κB signaling pathway. However, IL-1β increased and TNF-α decreased the levels of the long PRL receptor isoform in association with dual actions of PRL on SF inflammatory response. PRL reduced the proinflammatory effect and activation of NF-κB by IL-1β but increased TNF-α-induced inflammation and NF-κB signaling. The double-faceted role of PRL against the two cytokines manifested also in vivo. IL-1β or TNF-α with or without PRL were injected into the knee joints of healthy mice and joint inflammation was monitored after 24 hours. IL-1β and TNF-α increased the joint expression of proinflammatory factors and the infiltration of immune cells. PRL prevented the actions of IL-1β but was either inactive or further increased the proinflammatory effect of TNF-α. We conclude that PRL exerts opposite actions on joint inflammation in males and females that depend on specific proinflammatory cytokines, the level of the PRL receptor, and the activation of NF-κB signaling. Dual actions of PRL may help balance joint inflammation in RA and provide insights for development of new treatments.

Innate immune responses to enteric Escherichia colidictate neonatal sepsis outcomes

Abstract Late-onset neonatal sepsis (LOS), a leading cause of neonatal death, can result from pathogenic bacteria disseminating to the bloodstream from the intestinal microbiota. E. coliis the second most commonly isolated pathogen causing LOS. During sepsis, there are significant immune discrepancies between infants and adults, including elevated IL-6 levels in neonates, demonstrating the need for age-specific research. We have developed a murine model of LOS that uses clinical isolates of gut-resident E. coli, which results in rapid pro-inflammatory cytokine production within 6 hours and neonatal mortality within 2–3 days post-infection. Not all enteric E. coliresults in inflammation and mortality, and we have classified isolates as “commensal” or “pathogenic”. TLR4−/− mice infected with pathogenic E. colihave a delayed mortality to sepsis, suggesting innate bacterial recognition is required for acute inflammation. To further determine the source of this delay, we have begun investigating signaling pathways during bacterial infection. We found the immune signaling pathway NFκB/AP1 is consistently activated in murine macrophages by commensal and pathogenic bacterial strains. However, only pathogenic bacteria induce elevated IL-6 production by murine macrophages. Interestingly, this response required live bacteria, suggesting lipopolysaccharide alone from E. coliis not sufficient to recapitulate LOS inflammation. Our future directions will explore alternative signaling pathways that are activated uniquely during pathogenic infection and induce a robust inflammatory response. Through this work, we will determine the consequence of specific pro-inflammatory cytokines in neonatal mice during pathogenic infection. Research supported by R03 DK122187.

Analysis of intervertebral disc CCR6 and IL-6 gene levels with short-term postoperative low back pain after spinal fusion in lumbar degenerative disease.

Previous studies have reported that specific pro-inflammatory cytokines or chemokines are more highly expressed in painful than in nonpainful intervertebral discs (IVDs). However, few studies have investigated their correlation with postsurgical outcomes or the relationship between postoperative pain and inflammatory cytokines in IVDs. Thus, the present study examined the correlation among the gene expression levels of pro-inflammatory cytokines and chemokines in IVD tissues removed during surgery and low back pain (LBP), leg pain (LP), and leg numbness (LN) at one year after spinal fusion surgery in patients with a lumbar degenerative disease (LDD). Chemokine and cytokine gene expression levels were measured in IVD samples from 48 patients with LDD. The associations between chemokine and cytokine gene expression levels and pain intensity (numeric rating scale [NRS]) were also analyzed. A correlation analysis was performed between gene expression in each IVD and preoperative and postoperative pain intensity. In the preoperative analysis, CCR6 was associated with NRSLBP (r = -0.291, P = 0.045). Postoperative pain analysis revealed correlations between postoperative NRSLBP and CCR6 (r = -0.328, P = 0.023) and between postoperative NRSLBP and IL-6 (r = -0.382, P = 0.007). Furthermore, patients with high postoperative LBP intensity (NRSLBP ≥ 7) also had high LBP intensity (NRSLBP ≥ 6) before surgery, and a correlation was observed (r = 0.418, P = 0.003). None of the gene mRNAs correlated with NRSLP or NRSLN, respectively. CCR6 and IL-6 gene expression in the IVD was associated with postoperative LBP intensity and may indicate a need for postoperative pain management.

Immunological correlates of protection following vaccination with glucan particles containing Cryptococcus neoformans chitin deacetylases

Vaccination with glucan particles (GP) containing the Cryptococcus neoformans chitin deacetylases Cda1 and Cda2 protect mice against experimental cryptococcosis. Here, immunological correlates of vaccine-mediated protection were explored. Studies comparing knockout and wild-type mice demonstrated CD4+ T cells are crucial, while B cells and CD8+ T cells are dispensable. Protection was abolished following CD4+ T cell depletion during either vaccination or infection but was retained if CD4+ T cells were only partially depleted. Vaccination elicited systemic and durable antigen-specific immune responses in peripheral blood mononuclear cells (PBMCs), spleens, and lungs. Following vaccination and fungal challenge, robust T-helper (Th) 1 and Th17 responses were observed in the lungs. Protection was abrogated in mice congenitally deficient in interferon (IFN) γ, IFNγ receptor, interleukin (IL)-1β, IL-6, or IL-23. Thus, CD4+ T cells and specific proinflammatory cytokines are required for GP-vaccine-mediated protection. Importantly, retention of protection in the setting of partial CD4+ T depletion suggests a pathway for vaccinating at-risk immunocompromised individuals.

Machine Learning Prediction of Minor Depression Diagnostic Based on Specific Serologic Pro-Inflammatory Cytokines Variation in Non-Demented Geriatric Subjects

Machine Learning Prediction of Minor Depression Diagnostic Based on Specific Serologic Pro-Inflammatory Cytokines Variation in Non-Demented Geriatric Subjects

Analysis of selected pro-inflammatory cytokines: IL-1β, IL-6, CXCL-8, and TNF-α in children with seizure disorders during acute infection. Is there a specific pro-inflammatory cytokine profile in these patients?

Introduction and objective: This study aimed to analyse the levels of selected pro-inflammatory cytokines in children with seizures during acute infection. Materials and methods: The study was conducted in the Department of Infectious Diseases and Child Neurology of the Poznan University of Medical Sciences from 19 January 2017 to 5 December 2020. Pro-inflammatory cytokines were measured in 64 patients with febrile seizures and 11 patients after an epileptic seizure in generalised epilepsy. The control group comprised 46 patients with delayed development. Serum pro-inflammatory cytokines were determined using the BioLegend’s ELISA MAX™ Deluxe Set. Pathogens were detected by standard diagnostic methods. Total white blood cell count, C-reactive protein and procalcitonin were determined using standard diagnostic methods. Results: Significantly higher levels of all analysed pro-inflammatory cytokines were found in patients with simple and simple plus febrile seizures; interleukin 6, CXCL-8 in those with complex febrile seizures; interleukin 6, CXCL-8, tumour necrosis factor α following epileptic seizure. The intensity of the inflammatory response in simple and simple plus febrile seizure patients corresponded to significantly higher levels of all pro-inflammatory cytokines and inflammatory markers. Pro-inflammatory profiles differed depending on the aetiology of the infection. Significantly higher levels interleukin 6, CXCL-8, tumour necrosis factor α were found in simple and simple plus febrile seizure patients infected with human herpesvirus-6 compared to the control group. Conclusions: In patients with febrile seizures and epileptic seizures, the involvement of interleukin 1β, interleukin 6, CXCL-8, and tumour necrosis factor α was confirmed in the inflammatory process, with a different distribution in the analysed groups. Pro-inflammatory cytokine profiles varied depending on the infectious aetiology.

Persistent CD38 Expression on CD8 + T Lymphocytes Contributes to Altered Mitochondrial Function and Chronic Inflammation in People With HIV, Despite ART.

Age-associated comorbidities are higher in people with HIV (PWH) than HIV-negative individuals. This is partially attributed to immune activation and CD38 expression on T cells driving chronic inflammation. However, the exact contribution of CD38-expressing T cells on the proinflammatory response is not completely understood. CD38-expressing CD8 + T lymphocytes were measured from PWH and HIV-negative individuals. Mitochondrial mass, superoxide content, membrane depolarization of CD4 + and CD8 + T lymphocytes, and cytokine production after HIV(Gag)-specific peptide stimulation from CD38 + CD8 + T lymphocytes of PWH were measured to link biological effects of CD38 expression on cellular metabolism. The frequency of activated CD8 + CD38 + T cells persists in PWH on ART compared with HIV-negative individuals. Higher CD38 expression is associated with mitochondrial biogenesis and HIV(Gag)-specific proinflammatory cytokine production in PWH. Blockade of CD38 results in lower Gag-specific cytokine production. ART only partially reduced HIV-induced CD38 expression on CD8 + T cells. CD8 + CD38 + T cells are highly activated in vivo, and HIV-specific stimulation in vitro augments CD38 expression, contributing to a proinflammatory response despite virologic control with ART. Therefore, CD38 is a potential therapeutic target for mitigating chronic inflammation that likely drives cellular aging, comorbidities, and end-organ disease in PWH.