Interleukin-15 and high-intensity exercise: relationship with inflammation, body composition and fitness in cancer survivors.

Pre-clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth. These anti-oncogenic effects of exercise were associated with the exercise-mediated release of myokines such as interleukin (IL)-15. However, no study has quantified the acute IL-15 response in human cancer survivors, and whether physiological adaptations to exercise training (i.e. body composition and cardiorespiratory fitness) influence this response. In the present study breast, prostate and colorectal cancer survivors (n = 14) completed a single bout of high-intensity interval exercise (HIIE) [4×4 min at 85-95% heart rate (HR) peak, 3 min at 50-70% HR peak] before and after 7 months of three times weekly high-intensity interval training (HIIT) on a cycle ergometer. At each time point venous blood was sampled before and immediately after HIIE to assess the acute myokine (IL-15, IL-6, IL-10, IL-1ra) responses. Markers of inflammation, cardiorespiratory fitness and measures of body composition were obtained at baseline and 7 months. An acute bout of HIIE resulted in a significant increase in IL-15 concentrations (pre-intervention: 113%; P = 0.013, post-intervention: 102%; P = 0.005). Post-exercise IL-15 concentrations were associated with all other post-exercise myokine concentrations, lean mass (P = 0.031), visceral adipose tissue (P = 0.039) and absolute V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ peak (P = 0.032). There was no significant effect of 7 months of HIIT on pre- or post-HIIE IL-15 concentrations (P > 0.05). This study demonstrates HIIE is a sufficient stimulus to increase circulating IL-15 and other myokines including IL-6, IL-10 and IL-1ra which may be clinically relevant in the anti-oncogenic effect of exercise and repetitive exposure to these effects may contribute to the positive relationship between exercise and cancer recurrence. KEY POINTS: Exercise has been demonstrated to reduce the risk of cancer recurrence. Pre-clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth, mediated by exercise-induced myokines (IL-6 and IL-15). High-intensity interval exercise significantly increased myokines associated with the anti-oncogenic effect of exercise and the magnitude of response was associated with lean mass, but training did not appear to influence this response. Given IL-15 has been implicated in the anti-oncogenic effect of exercise and is being explored as an immunotherapy agent, high-intensity interval exercise may improve outcomes for people living beyond cancer through IL-15-mediated pathways. Interventions that increase lean mass may also enhance this response.

Prevention of prostate cancer metastasis by a CRISPR-delivering nanoplatform for interleukin-30 genome editing.

Prostate cancer (PC) is a leading cause of cancer-related deaths in men worldwide. Interleukin-30 (IL-30) is a PC progression driver, and its suppression would be strategic for fighting metastatic disease. Biocompatible lipid nanoparticles (NPs) were loaded with CRISPR-Cas9gRNA to delete the human IL30 (hIL30) gene and functionalized with anti-PSCA-Abs (Cas9hIL30-PSCA NPs). Efficiency of the NPs in targeting IL-30 and the metastatic potential of PC cells was examined in vivo in xenograft models of lung metastasis, and in vitro by using two organ-on-chip (2-OC)-containing 3D spheroids of IL30+ PC-endothelial cell co-cultures in circuit with either lung-mimicking spheroids or bone marrow (BM)-niche-mimicking scaffolds. Cas9hIL30-PSCA NPs demonstrated circulation stability, genome editing efficiency, without off-target effects and organ toxicity. Intravenous injection of three doses/13 days, or five doses/20 days, of NPs in mice bearing circulating PC cells and tumor microemboli substantially hindered lung metastasization. Cas9hIL30-PSCA NPs inhibited PC cell proliferation and expression of IL-30 and metastasis drivers, such as CXCR2, CXCR4, IGF1, L1CAM, METAP2, MMP2, and TNFSF10, whereas CDH1 was upregulated. PC-Lung and PC-BM 2-OCs revealed that Cas9hIL30-PSCA NPs suppressed PC cell release of CXCL2/GROß, which was associated with intra-metastatic myeloid cell infiltrates, and of DKK1, OPG, and IL-6, which boosted endothelial network formation and cancer cell migration. Development of a patient-tailored nanoplatform for selective CRISPR-mediated IL-30 gene deletion is a clinically valuable tool against PC progression.

Administration of Lacticaseibacillus casei CSL3 in Swiss Mice with Immunosuppression Induced by Cyclophosphamide: Effects on Immunological, Biochemical, Oxidative Stress, and Histological Parameters.

The study aimed to evaluate the effects of supplementation with Lacticaseibacillus casei CSL3 in Swiss mice immunosuppressed with cyclophosphamide on immunological, biochemical, oxidative stress, and histological parameters. The animals were distributed into four groups (control, CSL3, cyclophosphamide, and CSL3 + cyclophosphamide), where two groups were treated with L. casei CSL3 (10 log CFU mL-1) for 30 days, and two groups received chemotherapy (days 27 and 30-total dose of 250 mg kg-1). Counts of lactic acid bacteria (LAB) and bile-resistant LAB in stool samples; blood count (erythrogram, leukogram, and platelets); serum total cholesterol levels; catalase enzyme activity; and thiobarbituric acid reactive substances (TBARS) levels in liver, kidney, and brain; IL-4 expression; IL-23, TNF-α, NF-κß in the spleen; and histological changes in the liver, kidneys, and intestine were evaluated. The CSL3 + cyclophosphamide group showed a significant increase in bile-resistant LAB counts in feces (p = 0.0001), leukocyte counts, and expression of IL-23, TNF-α, and NF-κß (p < 0.05) significantly reduced total cholesterol levels (p = 0.001) and protected liver damage of supplemented animals. For oxidative stress damage, the bacterium did not influence the results. It is concluded that the bacterium is safe at a concentration of 10 log CFU mL-1 and has probiotic potential due to its positive influence on the immune response and lipid metabolism.

Can Selected Parameters of Brain Injury Reflect Neuronal Damage in Smoldering Multiple Sclerosis?

BACKGROUND: Inflammatory demyelination and impaired recovery processes result in permanent neurodegeneration and neurological disability in patients with multiple sclerosis (MS). In terms of smoldering MS, chronic neuroinflammation develops in the early period of the disease and leads to confirmed disability accumulation. There is a great need to identify biomarkers of neurodegeneration and disease progression. METHODS: A single-center prospective observational study was performed. The median age of the patients was 40 (31-52) years. Women comprised 64% of the study population. We evaluated the concentrations of the parameters of brain injury (NF-H, GFAP, S100B and UCHL1) in the cerebrospinal fluid (CSF) and the selected interleukins (ILs) in serum of 123 relapsing-remitting MS (RRMS) and 88 progressive MS (PMS) patients. RESULTS: The levels of GFAP, S100B and UCHL were higher in the PMS group than the RRMS group, in contrast to the levels of NF-H. We observed a positive correlation between the selected pro-inflammatory cytokines and the parameters of brain injury. The Expanded Disability Status Scale (EDSS) score increased with GFAP and NF-H levels and was correlated with the selected ILs. The concentrations of S100B, UCHL1 and NF-H reflected the duration of MS symptoms. CONCLUSIONS: The levels of brain injury parameters in the CSF and the selected serum ILs in MS patients seem to be promising biomarkers to determine neurodegeneration and neuroinflammation in smoldering MS. Further studies are warranted in this respect.

The Relationship between HERV, Interleukin, and Transcription Factor Expression in ZIKV Infected versus Uninfected Trophoblastic Cells.

Zika virus (ZIKV) is an arbovirus with maternal, sexual, and TORCH-related transmission capabilities. After 2015, Brazil had the highest number of ZIVK-infected pregnant women who lost their babies or delivered them with Congenital ZIKV Syndrome (CZS). ZIKV triggers an immune defense in the placenta. This immune response counts with the participation of interleukins and transcription factors. Additionally, it has the potential involvement of human endogenous retroviruses (HERVS). Interleukins are immune response regulators that aid immune tolerance and support syncytial structure development in the placenta, where syncytin receptors facilitate vital cell-to-cell fusion events. HERVs are remnants of ancient viral infections that integrate into the genome and produce syncytin proteins crucial for placental development. Since ZIKV can infect trophoblast cells, we analyzed the relationship between ZIKV infection, HERV, interleukin, and transcription factor modulations in the placenta. To investigate the impact of ZIKV on trophoblast cells, we examined two cell types (BeWo and HTR8) infected with ZIKV-MR766 (African) and ZIKV-IEC-Paraíba (Asian-Brazilian) using Taqman and RT2 Profiler PCR Array assays. Our results indicate that early ZIKV infection (24-72 h) does not induce differential interleukins, transcription factors, and HERV expression. However, we show that the expression of a few of these host defense genes appears to be linked independently of ZIKV infection. Future studies involving additional trophoblastic cell lineages and extended infection timelines will illuminate the dynamic interplay between ZIKV, HERVs, interleukins, and transcription factors in the placenta.

TNFα and IL-8 vitreous concentrations variations with two antidiabetic therapies in patients with proliferative diabetic retinopathy: an observational study.

BACKGROUND: Antidiabetic therapies are effective, but could indirectly modify the inflammatory response in the ocular microenvironment; therefore, a study was developed to evaluate the inflammatory cytokine profile in the vitreous humor of diabetic patients with retinopathy under treatment with antidiabetic drugs. METHODS: Observational, comparative, retrospective, cross-sectional study. Interleukins 1ß, 6, 8, 10, and tumor necrosis factor-alpha (TNFα) were evaluated in the vitreous humor obtained from patients with type 2 diabetes mellitus, proliferative diabetic retinopathy, and concomitant retinal detachment or vitreous hemorrhage, and who were already on antidiabetic treatment with insulin or metformin + glibenclamide. The quantification analysis of each cytokine was performed by the cytometric bead array (CBA) technique; medians and interquartile ranges were obtained, and the results were compared between groups using the Mann-Whitney U test, where a p-value < 0.05 was considered significant. RESULTS: Thirty-eight samples; quantification of TNFα concentrations was higher in the group of patients administered insulin, while interleukin-8 was lower; in the metformin + glibenclamide combination therapy group, it occurred inversely. In the stratified analysis, the highest concentrations of interleukin-8 and TNFα occurred in patients with vitreous hemorrhage; however, the only statistical difference existed in patients with retinal detachment, whose TNFα concentration in the combined therapy group was the lowest value found (53.50 (33.03-86.66), p = 0.03). Interleukins 1ß, 6, and 10 were not detected. CONCLUSION: Interleukin-8 and TNFα concentrations are opposite between treatment groups; this change is more accentuated in patients with proliferative diabetic retinopathy and vitreous hemorrhage, where the highest concentrations of both cytokines are found, although only TNFα have statistical difference.

Role of Interleukins in Pancreatic Cancer: A Literature Review.

PURPOSE: This review article summarizes the pathophysiological aspects of interleukins (ILs) including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, and IL-10 in pancreatic cancer (PC). METHODS: Science Direct, PubMed, and Google Scholar were used for the literature review. The search was conducted until August 12, 2024, and particular keywords such as "Pancreatic Cancer," "Interleukins," "Pathophysiological Aspects," "Immunosuppression," "Invasiveness," and "Metastasis" were used. Focusing on interleukins related to pancreatic cancer, 61 original studies were included: 32 studies for human patients, 16 studies for animal models, and 13 studies for both animal models and human patients. All types of PC were considered. The timeframe of 1991 to 2024 was chosen for clinical studies. RESULTS: In epithelial pancreatic tumors, IL-1 is a major inflammation factor. Serum concentrations of soluble interleukin-2-receptor were considerably greater in patients with PC and chronic pancreatitis than in healthy individuals. In comparison to controls, pancreatic cancer patients had considerably greater levels of macrophage colony-stimulating factor and significantly lower levels of stem cell factor and IL-3. The tissues and cells of pancreatic cancer have higher concentrations of IL-4 receptors. IL-5 has a role in the accumulation of pancreatic fibrosis. For individuals with pancreatic ductal adenocarcinoma (PDAC), a high serum level of IL-6 may be a separate risk factor for the development of widespread liver metastases. PDAC patients' peripheral blood mononuclear cells exhibit a substantial upregulation of IL-7 receptor. The role of IL-8 in the growth and spread of PC in humans. The miR-200a/ß-catenin axis may be the mechanism by which IL-9 stimulates the proliferation and metastasis of PC cells. Blocking IL-10 in the local microenvironment appears to result in a significant reversal of tumor-induced immunosuppression. CONCLUSION: The article concludes that interleukins 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 played significant roles in the pathogenesis of PC.

Common cytokine receptor gamma chain family cytokines activate MAPK, PI3K, and JAK/STAT pathways in microglia to influence Alzheimer's Disease.

Dementia is an umbrella term used to describe deterioration of cognitive function. It is the seventh leading cause of death and is one of the major causes of dependence among older people globally. Alzheimer's Disease (AD) contributes to approximately 60-70% of dementia cases and is characterized by the accumulation of amyloid plaques and tau tangles in the brain. Neuroinflammation is now widely accepted as another disease hallmark, playing a role in both the response to and the perpetuation of disease processes. Microglia are brain-resident immune cells that are initially effective at clearing amyloid plaques but contribute to the damaging inflammatory milieu of the brain as disease progresses. Circulating peripheral immune cells contribute to this inflammatory environment through cytokine secretion, creating a positive feedback loop with the microglia. One group of these peripherally derived cytokines acting on microglia is the common cytokine receptor γ chain family. These cytokines bind heterodimer receptors to activate three major signaling pathways: MAPK, PI3K, and JAK/STAT. This perspective will look at the mechanisms of these three pathways in microglia and highlight the future directions of this research and potential therapeutics.

The possible effects of chronic administration of amiodarone hydrochloride on the seminiferous tubules of adult male albino rats: histological and biochemical study.

Amiodarone hydrochloride is an antiarrhythmic agent that is widely prescribed. However, it has serious side effects that approximately affect the whole body organs. In our study, we aimed to assess the possible effects of chronic administration of two different doses of amiodarone hydrochloride on the oxidative and inflammatory parameters as well as the histological morphology and ultrastructure of the seminiferous tubules of adult male albino rats. Forty rats were divided into four groups; Control group 1: each rat did not receive any drugs at all. Control group 2: each rat received 3 ml of 0.16% methylcellulose, orally and daily for 4 weeks. Low dose amiodarone group: each rat received 3 ml of 0.16% methylcellulose contained 3.6 mg amiodarone, orally and daily for 4 weeks. High dose amiodarone group: each rat received 3 ml of 0.16% methylcellulose contained 7.2 mg amiodarone, orally and daily for 4 weeks. Blood samples were collected for measuring serum levels of malondialdehyde, superoxide dismutase, interleukin-6 and tumor necrosis factor-alpha. Testes specimens were examined to assess the morphological changes and the level of expression of caspase-3 apoptotic marker. The results indicated that; amiodarone hydrochloride could induce a dose-dependent toxicity, causing oxidative stress, inflammation, cellular degeneration, deposition of collagen and enhanced apoptosis in the seminiferous tubules.

Study of Inflammatory Biomarkers in Treatment-Naive HIV Patients and Their Correlation With Clusters of Differentiation 4 (CD4) Count.

Introduction The human immunodeficiency virus (HIV) primarily targets clusters of differentiation 4 (CD4)+ T cells and other immune cells, leading to immune dysfunction. Cytokines such as interleukin (IL)-23 and IL-27 have complex roles in HIV-associated disease progression, affecting viral replication and immune responses. This study aimed to explore the correlation between HIV-related CD4 lymphopenia and the inflammatory cytokines IL-23 and IL-27 in treatment-naive HIV patients.  Materials and methods This is a single-center, prospective, observational study conducted at the Antiretroviral Treatment (ART) Center of Jawaharlal Nehru Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India. Sixty-five treatment-naive HIV seropositive patients were recruited in this study. Quantitative estimation of inflammatory biomarkers (IL-23 and IL-27) was performed using enzyme-linked immunosorbent assay (ELISA). The fluorescent-activated cell sorter count (FACSCount) technology was used to determine the CD4+ T-cell count.  Results Our study revealed that HIV-infected individuals had significantly higher levels of IL-23 (868.9±246.7 pg/mL vs 98.3±86.6 pg/mL, p < 0.01) and IL-27 (1629.5±518.5 pg/mL vs 291.3±225.2 pg/mL, p < 0.01) compared to healthy controls. Additionally, we found a strong positive correlation between CD4 count and IL-23 titers (r = 0.93, p < 0.01), as well as between CD4 count and IL-27 titers (r = 0.92, p < 0.01) in HIV-positive individuals.  Conclusion The findings suggest that these cytokines respond to HIV infection and may potentially play a crucial role in restraining HIV replication and slowing down the progression of the disease.

Breadth and polyfunctionality of T cell responses to human cytomegalovirus in men who have sex with men: relationship with HIV infection and frailty.

Cytomegalovirus (CMV)-seropositive adults have large T cell responses to a wide range of CMV proteins; these responses have been associated with chronic inflammation and frailty in people with or without HIV infection. We analyzed the relationships between chronic HIV infection, frailty, and the breadth and polyfunctionality of CD4 and CD8 T cell responses to CMV. Peripheral blood mononuclear cells from 42 men (20 without HIV and 22 with virologically suppressed HIV) in the Multicenter AIDS Cohort Study (MACS) were stimulated with peptide pools spanning 19 CMV open reading frames (ORFs). As measured by flow cytometry and intracellular cytokine staining for IFN-γ, TNF-α, and IL-2, CD8 T cells from men with HIV responded to significantly more CMV ORFs than those from men without HIV. This was primarily due to a broader response to ORFs that are expressed during the late phase of CMV replication. The number of ORFs to which a participant's T cells responded was positively correlated with the sum of all that individual's T cell responses; these correlations were weaker in men with than without HIV. Polyfunctional CMV-specific CD4 responses (production of more than one cytokine) were significantly lower in men with than without HIV. Frailty status did not substantially affect the breadth or magnitude of the CMV-specific T cell responses. These results suggest that immune control of CMV infection is affected more by chronic HIV infection than by frailty. The differences between men with and without HIV were similar to those reported between young and older adults without HIV. IMPORTANCE: T cell responses to chronic cytomegalovirus (CMV) infection have significant biological and clinical implications in HIV infection and aging. Here, we systematically analyzed the breadth, magnitude, and polyfunctionality of T cell responses to multiple CMV antigens in men with and without HIV in the Multicenter AIDS Cohort Study (MACS), a longstanding study of the natural and treated history of HIV-1 infection in men who have sex with men. We found that the breadth and polyfunctionality of T cell responses to CMV were different between men with chronic, treated HIV and those without HIV. The reason for these differences is unknown, but these findings suggest that people with treated HIV may have more frequent CMV reactivation than people without HIV. Differences between people with and without HIV also resembled differences reported between young and older adults without HIV, supporting a role for the immune responses to CMV in the aging process.

Potential of salivary biomarkers for diagnosing and prognosing rheumatoid arthritis: A systematic review and meta-analysis: Salivary biomarkers in Rheumatoid Arthritis patients - A systematic review with Meta-analysis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder. Blood biomarkers, like rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), lack the sensitivity and specificity for early diagnosis, delaying treatment. This review while highlighting the need for new diagnostic tools, emphasizes the promising avenue of saliva for developing RA biomarkers. OBJECTIVE: This systematic review and meta-analysis assess the effectiveness of salivary biomarkers in the diagnosis and prognosis of RA, examining current evidence and proposing avenues for future research. METHODOLOGY: A literature review following PRISMA 2021 guidelines was conducted using PubMed, Scopus, Web of Science, and Google Scholar to identify studies from the past five years on salivary biomarkers in RA patients compared to healthy controls. RESULT: The review focused on original research articles, and meta-analysis was performed on studies reporting standard deviation values for inflammatory markers such as IL-6, IL-8, MMP-8, and TNF-alpha. The meta-analysis included eleven studies with 394 RA patients and 255 healthy controls, evaluating IL-8, IL-6, MMP-8, and TNF-α as RA biomarkers. IL-8 showed a mean difference of 7.32 (CI: -5.48 to 20.13), not statistically significant, favouring controls. IL-6 had a CI of -0.09 (CI: -2.20 to 2.02) with high heterogeneity (I² = 98%), suggesting its potential as a diagnostic and prognostic biomarker. TNF-α and MMP-8 showed no significant differences (CIs: 4.54 and 2.71, respectively). CONCLUSION: This systematic review and meta-analysis emphasize saliva's potential in identifying RA biomarkers, especially IL-6, which is associated with the disease's pathogenesis. However, significant evidence heterogeneity necessitates larger, multicentric studies for validation.

The Influence of Analgesic Wound Infiltration on Postoperative Pain and Inflammatory Cytokines in Open Colorectal Surgery: A Randomized Comparative Pilot Study.

Background and Objectives: Surgical wound analgesia has been analyzed in many studies, but few have focused on its relationship with inflammatory markers. As such, we aimed to determine the influence of analgesic surgical wound infiltration in open colorectal surgery on the seric levels of pro- and anti-inflammatory markers and the associated efficacy in postoperative pain control. Materials and Methods: Forty patients who underwent open colorectal surgery were prospectively randomized: group 0, epidural analgesia; group 1, intravenous analgesia (control), group 2, preincision and prelaparoraphy infiltration; and, group 3, prelaparoraphy infiltration. Wound infiltration was performed with ropivacaine. We analyzed the levels of IL-6 and IL-10 cytokines before and 6 h after surgery and their correlation with pain scores. Results: The postoperative Il-6 levels were significantly lower in group 0 than in the control (p = 0.041). The postoperative Il-10 levels were significantly higher in group 3 (p = 0.029) than in the control. Six hours after the operation, the pain scores were significantly lower in all groups than in the control (p = 0.005, p = 0.022, and p = 0.017 for groups 0, 2, and 3, respectively). Pain scores were significantly correlated with Il-10 levels in group 2 (p = 0.047); in group 3, IL-10 levels directly correlated with those of Il-6 (p = 0.026). Conclusions: The analgetic effect of preincisional and prelaparoraphy analgetic infiltration was efficient. The analgetic infiltration of the surgical wound prior to closure stimulates both the inflammatory activator and regulator interleukins.

[Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti-interleukins].

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gastrointestinal tract. The introduction of biologics, particularly anti-interleukin (IL) agents, has revolutionized IBD treatment. This review summarizes the role of ILs in IBD pathophysiology and describes the efficacy and positioning of anti-IL therapies. We discuss the functions of key ILs in IBD and their potential as therapeutic targets. The review then discusses anti-IL therapies, focusing primarily on ustekinumab (anti-IL-12/23), risankizumab (anti-IL-23), and mirikizumab (anti-IL-23). Clinical trial data demonstrate their efficacy in inducing and maintaining remission in Crohn's disease and ulcerative colitis. The safety profiles of these agents are generally favorable. However, long-term safety data for newer agents are still limited. The review also briefly discusses emerging therapies such as guselkumab and brazikumab. Network meta-analyses suggest that anti-IL therapies perform well compared to other biological agents. These agents may be considered first- or second-line therapies for many patients, especially those with comorbidities or safety concerns. Anti-IL therapies represent a significant advancement in IBD treatment, offering effective and relatively safe options for patients with moderate to severe disease.

Causality between various cytokines and asthma: a bidirectional two-sample Mendelian randomization analysis.

Background: Many studies have shown that cytokines play an important role in the pathogenesis of asthma, but their biological effects on asthma remain unclear. The Mendelian randomization (MR) method was used to evaluate the causal relationship between various cytokines [such as interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), colony-stimulating factors (CSFs), transforming growth factor (TGF), etc.,] and asthma. Methods: In this study, inverse variance weighting was used to evaluate the causal relationship between asthma and cytokines. In addition, the reliability of the results is ensured by multiple methods such as MR-Egger, weighted median, MR-Raps, MR-Presso, and RadialMR, as well as sensitivity analysis. Results: The results showed that none of the 11 cytokines was associated with the risk of asthma. In contrast, asthma can increase levels of IL-5 [odds ratio (OR) = 1.112, 95% confidence interval (CI): 1.009-1.224, P = 0.032] and IL-9 (OR = 1.111, 95% CI: 1.013-1.219, P = 0.025). Conclusion: Genetically predicted asthma was positively associated with elevated levels of IL-5 and IL-9, indicating the downstream effects of IL-5 and IL-9 on asthma. Medical treatments can thus be designed to target IL-5 and IL-9 to prevent asthma exacerbations.

Immunology of Cytokine Storm Syndromes: Natural Killer Cells.

Natural killer (NK) cells are innate immune lymphocytes that rapidly produce cytokines upon activation and kill target cells. NK cells have been of particular interest in primary hemophagocytic lymphohistiocytosis (pHLH) since all of the genetic defects associated with this disorder cause diminished cytotoxic capacity of NK cells and T lymphocytes, and assays of NK cell killing are used clinically for the diagnosis of HLH. Herein, we review human NK cell biology and the significance of alterations in NK cell function in the diagnosis and pathogenesis of HLH.

Biochemical implication of acetylcholine, histamine, IL-18, and interferon-alpha as diagnostic biomarkers in hepatitis C virus, coronavirus disease 2019, and dual hepatitis C virus-coronavirus disease 2019 patients.

Globally, hepatitis C virus (HCV) and coronavirus disease 2019 (COVID-19) are the most common causes of death due to the lack of early predictive and diagnostic tools. Therefore, research for a new biomarker is crucial. Inflammatory biomarkers are critical central players in the pathogenesis of viral infections. IL-18, produced by macrophages in early viral infections, triggers inflammatory biomarkers and interferon production, crucial for viral host defense. Finding out IL-18 function can help understand COVID-19 pathophysiology and predict disease prognosis. Histamine and its receptors regulate allergic lung responses, with H1 receptor inhibition potentially reducing inflammation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. angiotensin-converting enzyme 2 (ACE-2) receptors on cholangiocytes suggest liver involvement in SARS-CoV-2 infection. The current study presents the potential impact of circulating acetylcholine, histamine, IL-18, and interferon-Alpha as diagnostic tools in HCV, COVID-19, and dual HCV-COVID-19 pathogenesis. The current study was a prospective cross-section conducted on 188 participants classified into the following four groups: Group 1 COVID-19 (n = 47), Group 2 HCV (n = 47), and Group 3 HCV-COVID-19 patients (n = 47), besides the healthy control Group 4 (n = 47). The levels of acetylcholine, histamine, IL-18, and interferon-alpha were assayed using the ELISA method. Liver and kidney functions within all groups showed a marked alteration compared to the healthy control group. Our statistical analysis found that individuals with dual infection with HCV-COVID-19 had high ferritin levels compared to other biomarkers while those with COVID-19 infection had high levels of D-Dimer. The histamine, acetylcholine, and IL-18 biomarkers in both COVID-19 and dual HCV-COVID-19 groups have shown discriminatory power, making them potential diagnostic tests for infection. These three biomarkers showed satisfactory performance in identifying HCV infection. The IFN-Alpha test performed well in the HCV-COVID-19 group and was fair in the COVID-19 group, but it had little discriminative value in the HCV group. Moreover, our findings highlighted the pivotal role of acetylcholine, histamine, IL-18, and interferon-Alpha in HCV, COVID-19, and dual HCV-COVID-19 infection. Circulating levels of acetylcholine, histamine, IL-18, and interferon-Alpha can be potential early indicators for HCV, COVID-19, and dual HCV-COVID-19 infection. We acknowledge that further large multicenter experimental studies are needed to further investigate the role biomarkers play in influencing the likelihood of infection to confirm and extend our observations and to better understand and ultimately prevent or treat these diseases.

STAT4 and STAT6, their role in cellular and humoral immunity and in diverse human diseases.

Signal transducer and activator of transcription (STAT) 4 and STAT6 play a crucial role in immune cells by transducing signals from specific cytokine receptors, and inducing transcription of genes involved in cell-mediated and humoral immunity. These two different defense mechanisms against pathogens are regulated by two specific CD4+ T helper (Th) cells known as Th1 and Th2 cells. Many studies have shown that several diseases including cancer, inflammatory, autoimmune and allergic diseases are associated with a Th1/Th2 imbalance caused by increased or decreased expression/activity of STAT4 or STAT6 often due to genetic and epigenetic aberrances. An altered expression of STAT4 has been observed in different tumors and autoimmune diseases, while a dysregulation of STAT6 signaling pathway is frequently observed in allergic conditions, such as atopic dermatitis, allergic asthma, food allergy, and tumors such as Hodgkin and non-Hodgkin lymphomas. Recently, dysregulations of STAT4 and STAT6 expression have been observed in SARS-CoV2 and monkeypox infections, which are still public health emergencies in many countries. SARS-CoV-2 can induce an imbalance in Th1 and Th2 responses with a predominant activation of STAT6 in the cytosol and nuclei of pneumocytes that drives Th2 polarization and cytokine storm. In monkeypox infection the virus can promote an immune evasion by inducing a Th2 response that in turn inhibits the Th1 response essential for virus elimination. Furthermore, genetic variations of STAT4 that are associated with an increased risk of developing systemic lupus erythematosus seem to play a role in defense against SARS-CoV-2 infection.

Signal transducer and activator of transcription (STAT) proteins are important and complex regulators of transcription that mediate many aspects of cellular immunity, proliferation, apoptosis and differentiation. STAT proteins are phosphorylated/activated in the cytoplasm by Janus Kinases (JAKs) a family of nonreceptor tyrosine kinases associated to type I and type II cytokine receptors. There are seven STAT family members that have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. STAT4 is activated by IL-12 after binding with its specific receptor and induces the production in Th1 cells of IFN-γ, which allows these cells to be particularly effective in protecting against viruses and intracellular bacteria. STAT6 is activated by IL-4 and IL-13 and is required for the development of Th2 immune response and for the production of Th2 cytokines IL-4, IL-5, and IL-13 that contribute to humoral response with the synthesis of antigen specific antibodies in B cells. Although STAT4 plays an important role in many physiological functions, an altered expression of this transcription factor, often due to genetic and epigenetic aberrances, has been observed in different tumors and autoimmune diseases. Dysregulation of STAT6 signaling pathway, often caused by genetic mutations in the STAT6 gene, has been observed in several allergic conditions and tumors such as Hodgkin and non-Hodgkin lymphomas.

[Features of inflammatory endotypes and phenotypes in chronic rhinosinusitis]. / Osobennosti endotipov i fenotipov vospaleniya pri khronicheskom rinosinusite.

Recently, significant progress has been made in identifying the cellular and molecular mechanisms responsible for the pathogenesis of chronic rhinosinusitis (CRS). Cohort studies of CRS have led to advances in the clinical understanding of this disease. New therapeutic agents have been approved or are undergoing clinical trials to expand treatment options for this disease. One of the promising areas in medicine is the provision of personalized clinical care. From this perspective, CRS can be divided into three different endotypes depending on the type of underlying inflammatory response. In the United States, CRS with and without nasal polyps is predominantly characterized as the second inflammatory endotype. CRS with nasal polyps (about 17%) and without nasal polyps (up to 20%) belongs to the 1st and 3rd inflammatory endotypes, respectively. And if for the second inflammatory endotype the effectiveness of targeted biological therapy is beyond doubt, then for the first and third inflammatory endotypes the principles of such conservative therapy are under active development. Moreover, large validated studies to confirm associations between CRS phenotypes and endotypes, as well as to find effective biological markers of inflammatory endotypes, remain to be performed.

Subcutaneous adipose tissue: Implications in dermatological diseases and beyond.

Subcutaneous adipose tissue (SAT) is the deepest component of the three-layered cutaneous integument. While mesenteric adipose tissue-based immune processes have gained recognition in the context of the metabolic syndrome, SAT has been traditionally considered primarily for energy storage, with less attention to its immune functions. SAT harbors a reservoir of immune and stromal cells that significantly impact metabolic and immunologic processes not only in the skin, but even on a systemic level. These processes include wound healing, cutaneous and systemic infections, immunometabolic, and autoimmune diseases, inflammatory skin diseases, as well as neoplastic conditions. A better understanding of SAT immune functions in different processes, could open avenues for novel therapeutic interventions. Targeting SAT may not only address SAT-specific diseases but also offer potential treatments for cutaneous or even systemic conditions. This review aims to provide a comprehensive overview on SAT's structure and functions, highlight recent advancements in understanding its role in both homeostatic and pathological conditions within and beyond the skin, and discuss the main questions for future research in the field.