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Leukemia inhibitory factor (LIF) is induced in inflammation and likely plays a regulatory role. Using LIF-deficient mice (LIF−/−), we report here that endogenous LIF has a protective role in endotoxic shock and host defence. LIF−/− mice have heightened sensitivity to LPS in a LPS/D-galactosamine (D-Gal) sensitization model compared to wild-type mice (LIF+/+), enhanced thrombocytopenia and leukopenia, with increased hepatic necrosis, neutrophil sequestration in the lung and accelerated mortality. These findings correlated with 10-fold higher tumour necrosis factor-α (TNFα) and interleukin-6 (IL-6) serum levels and reduced IL-10 production in LIF−/− mice in response to LPS. Therefore, endogenous LIF attenuates the endotoxic shock response, enhances the expression of basal acute phase proteins and IL-10 production, which downregulates TNFα synthesis and release and thereby confers partial protection to endotoxemia.

Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P  = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P  < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).

To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and they must be predictive of future health status. In 2009, the Nutrition and Immunity Task Force of the International Life Sciences Institute, European Branch, organized an expert group to attempt to identify robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population. Inflammation is a normal process and there are a number of cells and mediators involved. These markers are involved in, or are produced as a result of, the inflammatory process irrespective of its trigger and its location and are common to all inflammatory situations. Currently, there is no consensus as to which markers of inflammation best represent low-grade inflammation or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses. There are a number of modifying factors that affect the concentration of an inflammatory marker at a given time, including age, diet and body fatness, among others. Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative compared with data related to the concentration change in response to a challenge. A number of inflammatory challenges have been described. However, many of these challenges are poorly standardised. Patterns and clusters may be important as robust biomarkers of inflammation. Therefore, it is likely that a combination of multiple inflammatory markers and integrated readouts based upon kinetic analysis following defined challenges will be the most informative biomarker of inflammation.

In response to vaccination and/or infectious agents, the liver produces acute-phase proteins (APPs) driven by IL-6, which circulate in blood plasma as components of the humoral innate defense. This study investigates the liver of mice for possible effects of protective vaccination against primary blood-stage infections of Plasmodium chabaudi malaria on the expression of genes encoding APPs and IL-6 family members. Female Balb/c mice were vaccinated with a non-infectious vaccine prior to challenge with 106 P. chabaudi-infected erythrocytes, resulting in about 80% survival of otherwise lethal infections. Gene expression microarrays were used to determine the relative transcript levels of genes in the livers of vaccinated and unvaccinated mice on days 0, 1, 4, 8, and 11 p.i. (post infectionem). Vaccination induced significant (p-value < 0.05) differences in the expression of malaria-responsive genes toward the end of crisis on day 11 p.i., when mice recovered from infections. These genes include Saa4, Apcs, Cp, and Crp, encoding APPs described to inhibitorily interact with parasitic blood stages; the genes F2, F7, F8, F9, F10, and F13b, and Plg, Plat, and Serpina5, encoding proteins balancing coagulation vs. fibrinolysis dysregulated by malaria, respectively; the genes Hc, C8a, C8b, C8g, and C9, encoding components of lytic complement membrane attack complex (MAC); and Cfh, Cfi, and C4bp, encoding complement-regulatory proteins. Vaccination accelerated, albeit differently, the malaria-induced activation of all three complement pathways, evidenced as higher transcript levels of C1qa, C1qb, C1qc, Fcna, Cfp, C3, Cfh, C8a, and C9 on day 4 p.i., C1ra, C1s, and C2 on day 1 p.i., and Serping1, encoding the multifunctional protease inhibitor C1INH, on day 0 p.i. Protective vaccination may also accelerate downregulation of the malaria-promoting lethality of IL-6 trans-signaling, which may contribute to an overall accelerated recovery of mice from otherwise lethal blood-stage malaria.

Alternative polyadenylation results in different 3’ isoforms of messenger RNA (mRNA) transcripts. Alternative polyadenylation in the 3’ untranslated region (3’UTR) can alter RNA localization, stability and translational efficiency. The SERPINA1 mRNA has two distinct 3’ UTR isoforms, both of which express the protease inhibitor α-1-antitrypsin (A1AT). A1AT is an acute phase protein that is expressed and secreted from liver hepatocytes and upregulated during inflammation. Low levels of A1AT in the lung contributes to chronic obstructive pulmonary disease, while misfolding of A1AT in the liver contributes to liver cirrhosis. We analyzed the dynamics of alternative polyadenylation during cellular stress by treating the liver cell line HepG2 with the cytokine interleukin 6 (IL-6), ethanol or peroxide. SERPINA1 is transcriptionally upregulated after IL-6 treatment and has altered polyadenylation, resulting in an increase in long 3’UTR isoforms. We find that the long 3’UTR represses endogenous A1AT protein expression even with high levels of SERPINA1 mRNA. SERPINA1 expression and 3’ end processing are not affected by ethanol or peroxide. IL-6-induced changes in transcriptome-wide transcriptional regulation suggest changes to the endoplasmic reticulum and in secretory protein processing. Our data shows that inflammation influences polyA site choice for SERPINA1 transcripts, resulting in reduced A1AT protein expression.

Objective: Prostate tumors, if prostate cancer or adenoma, represent a major public health challenge. Progress in research on inflammation has revealed a connection between inflammation, immunity, and cancer. In this context, this study aimed to find IL-6 signaling systemic abnormalities in the inflammatory tumor microenvironment. Material and methods: This study was case–controlled, multicentered, and included 86 patients, 43 diagnosed with BPH and 43 diagnosed with PCa, between January 2019 and January 2020. The study group was homogenous and the studied parameters were IL-6 complex (IL-6, soluble receptor IL-6R, soluble glycoprotein gp130), acute phase proteins (C reactive protein—CRP, acid alpha1 glycoprotein—AGPA, ferritin, albumin, transferrin), and oxidative stress-associated variables (malondialdehyde—MDA, carbonylated protein—PCO, 8-hydroxy-deoxy guanosine-8-OHdG, total antioxidant status—bTAS). Results: The inflammatory microenvironment determined IL-6 signaling alterations (over-regulation of sIL-6R and suppression of sgp130 in PCa versus BPH), changes in acute phase reaction markers (increased serum levels of CRP, AGPA, ferritin, and decreased serum levels of albumin, transferrin) that were much more evident in PCa compared to BPH, an imbalance between macromolecular oxidative damage (MDA, PCO, 8-OHdG) and endogenous antioxidants (TAS) that was more accentuated in PCa compared with BPH, and a representative association between the sIL-6R/sgp130 ratio and inflammatory/oxidative stress-related factors only in PCa patients. Conclusions: Our study reconfirms the anterior concept that IL-6 promotes prostatic tumorigenesis. In this study, we first demonstrated that a high sIL-6R/sgp130 ratio facilitates prostate malignancy.

Interleukin-6 (IL-6) is a multifunctional cytokine with an essential role in immunity, inflammation, and cancer. Produced by immune, stromal and epithelial cells in response to infection or tissue stress, IL-6 regulates immune responses, acute-phase proteins (including serum amyloid A and C-reactive protein), hematopoiesis, and tissue remodeling. These effects are mediated via classical and trans-signaling pathways, which activate key intracellular cascades such as JAK/STAT3, MAPK, and PI3K/AKT. Accumulating evidence implicates dysregulated IL-6 signaling in both oncologic and infectious diseases, where it contributes to disease progression, immune evasion, and therapeutic resistance. This review aims to critically examine the role of IL-6 as a biomarker and therapeutic target in these two major clinical contexts: in cancer, IL-6 levels reflect tumor burden, prognosis, and therapy resistance in both adult and pediatric patients; in infectious diseases, circulating IL-6 may support early diagnosis and risk stratification, particularly in vulnerable pediatric populations. By integrating molecular mechanisms with clinical evidence, this review highlights IL-6 as a unifying biomarker linking inflammation, infection, and malignancy. It also addresses current limitations, including assay variability, lack of standardized reference ranges, especially in children, and challenges in clinical implementation.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy of B-cells frequently encountered among people living with HIV. Immunological abnormalities are common in immunocompetent individuals with DLBCL, and are often associated with poorer outcomes. Currently, data on derangements of immunological proteins, such as cytokines and acute phase reactants, and their impact on outcomes in HIV-associated DLBCL (HIV-DLBCL) is lacking. This study assessed the levels and prognostic relevance of interleukin (IL)-6, IL-10 and Transforming Growth Factor Beta (TGFβ), the acute phase proteins C-reactive protein (CRP) and ferritin; serum free light chains (SFLC) (elevation of which reflects a prolonged pro-inflammatory state); and the activity of the immunosuppressive enzyme Indoleamine 2,3-dioxygenase (IDO)in South African patients with DLBCL. Seventy-six patients with incident DLBCL were enrolled, and peripheral blood IL-6, IL-10, TGFβ, SFLC and IDO-activity measured in selected patients. Additional clinical and laboratory findings (including ferritin and CRP) were recorded from the hospital records. Sixty-one (80.3%) of the included patients were people living with HIV (median CD4-count = 148 cells/ul), and survival rates were poor (12-month survival rate 30.0%). The majority of the immunological proteins, except for TGFβ and ferritin, were significantly higher among the people living with HIV. Elevation of IL-6, SFLC and IDO-activity were not associated with survival in HIV-DLBCL, while raised IL-10, CRP, ferritin and TGFβ were. On multivariate analysis, immunological proteins associated with survival independently from the International Prognostic Index (IPI) included TGFβ, ferritin and IL-10. Derangements of immunological proteins are common in HIV-DLBCL, and have a differential association with survival compared to that reported elsewhere. Elevation of TGFβ, IL-10 and ferritin were associated with survival independently from the IPI. In view of the poor survival rates in this cohort, investigation of the directed targeting of these cytokines would be of interest in our setting.

Background/Objectives: Depression is associated with an increased risk for the development and progression of cardiovascular disease. This research investigated the association between depressive symptoms and inflammation in the development of atherosclerotic coronary events. Methods: This retrospective observational study included 276 patients who were not previously diagnosed with atherosclerotic coronary artery disease at the beginning of the research. Participants were categorized using the Hamilton Depression Rating Scale (HDRS) and the Structured Clinical Interview for DSM-5 (SCID) into two groups: the depression group and the control group. Inflammatory biomarkers (C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and cortisol) were measured at the beginning of the study, as well as at six months, one year, and two years. Results: Among patients with mild depression (17.3% vs. 4.2%) or moderate depression (15.4% vs. 6.7%), there were significantly more men than women, while among patients with very severe depression, there were significantly more women than men (21.7% vs. 11.5%). Participants with depression showed significantly higher increases at 2 years compared to baseline for all investigated parameters (p < 0.001). Depressed patients were significantly associated with an acute coronary syndrome (p = 0.038). Conclusions: This research highlights that individuals with depression face a greater risk of developing an acute coronary syndrome than those without depression.

Citral is the main ingredient of the lemongrass plant with anti-inflammatory properties. In this study, the effects of citral on reducing inflammation in experimental diabetes in rats were investigated. Forty rats were randomly divided into four groups. There were two control groups (healthy controls (H) and citral alone-treated control (HC)) and two diabetic groups (diabetes (D) and diabetes+citral treatment (DC)). After diabetes confirmation on day 7, treatment with citral (300 mg/kg) was started for 2 weeks by gavage in the DC and HC groups. On days 0, 7, and 21 of the study, inflammatory elements of blood serum, IL-6, TNF-α, haptoglobin, and α2-macroglobulin were compared between the four groups. Also, on day 21 of the study, the expression level of IL-6 and TNF-α in the liver tissue was analyzed by quantitative real-time PCR. On day 21 of the study, following treatment with citral for 14 days, there was a significant difference in the DC group’s inflammatory factors compared to the D group ( P < 0.005). However, no significant difference was observed in DC and the two control groups’ inflammatory factors. Regarding gene expression, the levels of IL-6 and TNF-α in the liver were significantly downregulated in the DC group compared to those in the D group ( P < 0.05). According to the results of this study, citral can be used as a suitable ingredient to reduce the inflammatory complications of diabetes.