Factors of Interleukin-6 Signaling in COVID-19 Patients with Lung Damage of Varying Degrees: A Pilot Study.

Specific features of IL-6 signal transduction were studied in 89 patients with lung damage of varying degrees during the first COVID-19 pandemic wave. The levels of IL-6 signaling components (IL-6, sIL-6R, and sgp130) and highly sensitive C-reactive protein (hsCRP) were examined in patients with intact lungs (CT-0), mild (CT-1), moderate (CT-2), moderate to severe (CT-3), and severe (CT-4) lung damage. Seventy patients were re-examined 3-7 months after discharge from the hospital. The IL-6 and hsCRP levels increased several times with severing lung damage severity. In patients with CT-3, sIL6-R increased statistically significantly and remained high in CT-4 patients. sgp130 levels were lower in CT-1 and CT-2 patients and higher in CT-3 and CT-4 patients compared to CT-0 patients. We revealed a positive correlation between IL-6 and hsCRP levels in CT-1, CT-2, and CT-3 patients. In CT-3 patients, sIL-6R levels positively correlated with IL-6 concentration. The studied parameters decreased considerably in all patients 3-7 months after discharge. It can be suggested that IL-6 classic-signaling is predominant in CT-1 and CT-2, while trans-signaling prevails in CT-3. Disorders in regulatory mechanisms of IL-6 signaling occur in CT-4, which prevents physiological elimination of IL-6 hyperactivity. The results obtained are preliminary and require a broader study.

Investigation of the causal relationship between Interleukin-6 signaling and gastrointestinal tract cancers: A Mendelian randomization study.

BACKGROUND: Observational studies indicate that interleukin-6(IL-6) has been associated with gastrointestinal tract cancers. However, the causal association is still confusing. Thus, we aimed to putative the causality between IL-6 signaling and gastrointestinal tract cancers. METHODS: We conducted a two-sample Mendelian randomization analysis to assess the causal effects. Two groups of IL-6 signaling-related single nucleotide polymorphisms were chosen from two Genome-wide association studies. Summary-level data for gastrointestinal tract cancers including esophageal, gastric, and colorectal cancer, were obtained from the FinnGen consortium and UK Biobank study. We also performed survival analysis to explore the prognostic value of IL-6 in gastrointestinal tract cancers. RESULTS: Genetically predicted plasma sIL6R level, which inhibits IL-6 Signaling, was associated with a reduced risk of gastric cancer in FinnGen. In the combined analysis of the two sources, genetically predicted sIL6R was associated with a decreased risk of gastric cancer (OR = 0.943, 95%CI: 0.904,0.983, p = 0.006). Survival analysis results indicated the prognostic value of IL-6 in gastric cancer. CONCLUSIONS: These results present evidence indicating that genetically-determined reduced IL-6 signaling lowers the risk of gastric cancer, which may provide potential prevention and therapeutic strategies for gastric cancer. Additionally, IL-6 may be a prognostic biomarker for gastric cancer.

Role of interleukin 6 and its soluble receptor on the diffusion barrier dysfunction of alveolar tissue.

During respiratory infection, barrier dysfunction in alveolar tissue can result from "cytokine storm" caused by overly reactive immune response. Particularly, interleukin 6 (IL-6) is implicated as a key biomarker of cytokine storm responsible for and further progression to pulmonary edema. In this study, alveolar-like tissue was reconstructed in a microfluidic device with: (1) human microvascular lung endothelial cells (HULEC-5a) cultured under flow-induced shear stress and (2) human epithelial cells (Calu-3) cultured at air-liquid interface. The effects of IL-6 and the soluble form of its receptor (sIL-6R) on the permeability, electrical resistance, and morphology of the endothelial and epithelial layers were evaluated. The diffusion barrier properties of both the endothelial and epithelial layers were significantly degraded only when IL-6 treatment was combined with sIL-6R. As suggested by recent review and clinical studies, our results provide unequivocal evidence that the barrier dysfunction occurs through trans-signaling in which IL-6 and sIL-6R form a complex and then bind to the surface of endothelial and epithelial cells, but not by classical signaling in which IL-6 binds to membrane-expressed IL-6 receptor. This finding suggests that the role of both IL-6 and sIL-6R should be considered as important biomarkers in developing strategies for treating cytokine storm.

A comparison of serum inflammatory parameters in progressive forms of multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system. Primary progressive MS (PPMS) is diagnosed in approximately 10-15 % of MS patients. Disease-modifying therapies (DMT) are less effective in modifying the course of progressive types of MS. It seems that inflammatory processes differ in the MS subtypes. OBJECTIVES: The objective of this study was to assess differences in the inflammatory parameters between PPMS and other courses of MS. MATERIALS AND METHODS: A total of 84 subjects were included in the study. The study group was divided according to the course of MS into the following categories: PPMS (n = 24); SPMS-secondary progressive multiple sclerosis (n = 14); RRMS-relapsing-remitting multiple sclerosis (n = 46). PPMS patients were further divided into treated with ocrelizumab and treatment-naive groups. The concentrations of serum inflammatory parameters were evaluated. RESULTS: PPMS and SPMS significantly differed in the serum levels of sCD30, gp130, sIL-6R alpha, osteopontin, pentraxin-3 and sTNF-R1. The serum concentrations of IFN-alpha2, IL-10, IL-20, IL-29 and osteopontin significantly differed between PPMS and RRMS. The serum levels of BAFF, IL-19, IL-20, pentraxin-3, s-TNF-R1 and s-TNF-R2 significantly differed between PPMS treated with ocrelizumab and treatment-naive. CONCLUSION: Although inflammatory processes take part in the pathogenesis of all types of MS, they differ between MS courses. Serum inflammatory parameters seem to be promising biomarkers in helping to differentiate courses of MS, and in assessing reactions to DMT treatment. Further investigations on their usage are required.

Cytokine status and significant increase of IL-6 and sIL-6R in the aqueous humor of diabetic cataract patients revealed by quantitative multiplexed assays.

OBJECTIVE: This study aimed to investigate inflammatory cytokine expression profiles in the aqueous humor (AH) of diabetic cataract (DC) patients. METHODS: A quantitative multiplexed antibody assay was performed to measure the expression levels of 40 inflammatory cytokines in AH samples from DC and age-related cataract (ARC) patients. Bioinformatics analysis was used to examine the functions of the cytokines. Enzyme-linked immunosorbent assays (ELISAs) and western blots were performed to verify the data. RESULTS: The multiplexed antibody assay revealed that the expression levels of IL-6, sIL-6R, IL-17A, IL-8, MCP-1, TNF-ß, RANTES, TIMP-1, and TIMP-2 were higher in the AH of DC patients compared with ARC patients. However, IL-1ra and IL-1a expression levels were lower in the DC patient AH samples. Pathway analysis indicated that IL-6 and sIL-6R belong to the class I helical cytokine family, which is associated with many biological functions. ELISA and western blot results confirmed that IL-6R and IL-6 expression levels were significantly higher in DC patients compared with ARC patients. CONCLUSIONS: Our results revealed the status of 40 inflammatory cytokines in the AH by quantitative multiplexed assays. Additionally, IL-6 and sIL-6R were expressed markedly higher in DC compared with ARC, which may play critical roles in DC pathophysiology.

Evaluation of systemic IL-6 trans-signalling in patients with primary open-angle glaucoma.

PURPOSE: To evaluate systemic trans-signalling of interleukin (IL)-6 in patients with primary open-angle glaucoma (POAG). METHODS: Fifty-one POAG patients and 47 matched healthy controls were enrolled. Serum concentrations of IL-6, sIL-6R, and sgp130 were quantified. RESULTS: Serum levels of IL-6, sIL-6R, and IL-6/sIL-6R ratios in the POAG group were significantly higher than those in control group, while only the sgp130/sIL-6R/IL-6 ratio was decreased. Among POAG subjects, advanced-stage patients exhibited significantly higher intraocular pressure (IOP), serum IL-6 and sgp130 levels, and IL-6/sIL-6R ratio than those in the early to moderate stage. The ROC curve analysis revealed that the IL-6 level and IL-6/sIL-6R ratio performed better than other parameters in diagnosing POAG and discriminating POAG severity. Serum IL-6 level was moderately correlated with IOP and C/D ratio, while a weak correlation was observed between sIL-6R levels with C/D ratio. IL-6 and sIL-6R levels were correlated with each other in POAG patients but not in healthy controls. CONCLUSION: Overstimulation of systemic IL-6 trans-signalling has been implicated in POAG.

Mendelian randomization study on causal association of IL-6 signaling with pulmonary arterial hypertension.

BACKGROUND: A recent Mendelian randomization (MR) did not support an effect of the lead interleukin-6 receptor (IL-6 R) variant on risk of pulmonary arterial hypertension (PAH). Thus, we used two sets of genetic instrumental variants (IVs) and publicly available PAH genome-wide association studies (GWAS) to reassess the genetic causal link between IL-6 signaling and PAH. METHODS: Six independent IL-6 signaling and 34 independent soluble IL-6 receptor (sIL-6 R) genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. RESULTS: We found that as IL-6 signaling genetically increased, the risk of PAH reduced using IVW (odds ratio [OR] = 0.023, 95% confidence interval [CI]: 0.0013-0.393; p = .0093) and weighted median (OR = 0.033, 95% CI: 0.0024-0.467; p = .0116). Otherwise, as sIL-6 R genetically increased, the risk of PAH increased using IVW (OR = 1.34, 95% CI: 1.16-1.56; p = .0001), weighted median (OR = 1.36, 95% CI: 1.10-1.68; p = .005), MR-Egger (OR = 1.43, 95% CI: 1.05-1.94; p = .03), and weighted mode (OR = 1.35, 95% CI for OR: 1.12-1.63; p = .0035). CONCLUSION: Our analysis suggested the causal link between genetically increased sIL-6 R and increased risk of PAH and between genetically increased IL-6 signaling and reduced risk of PAH. Thus, higher sIL-6 R levels may be a risk factor for patients with PAH, whereas higher IL-6 signaling may be a protective factor for patients with PAH.

Mendelian Randomization Study on Causal Association of IL-6With Breast Cancer.

BACKGROUND: Previous studies have shown an important role of interleukin 6 (IL-6) in the progression and metastasis of breast cancer. The present 2-sample Mendelian randomization (MR) study aimed to identify the genetic causal link between IL-6 and breast cancer. MATERIAL AND METHODS: IL-6-signaling and its negative regulator soluble IL-6 receptor (sIL-6R) genetic instruments were chosen from 2 large-scale genome-wide association studies (GWAS) of 204,402 and 3,301 European individuals, respectively. GWAS for breast cancer (14,910 cases and 17,588 controls of European ancestry) was used to evaluate the effect of IL-6-signaling- or sIL-6R-associated genetic instrumental variants on breast cancer risk by performing a 2-sample MR study. RESULTS: As IL-6-signaling genetically increased, breast cancer risk increased based on weighted median (odds ratio [OR] = 1.396, 95% confidence interval [CI]: 1.008-1.934, P = .045) and inverse variance weighted (IVW) (OR = 1.370, 95% CI: 1.032-1.819, P = .030). Otherwise, as sIL-6R genetically increased, the risk of breast cancer decreased based on weighted median (OR = 0.975, 95% CI: 0.947-1.004, P = .097) and IVW (OR = 0.977, 95% CI: 0.956-0.997, P = .026). CONCLUSION: Our analysis suggests a causal link between a genetically-linked increase in IL-6-signaling and increase in the risk of breast cancer. Thus, inhibition of IL-6 may be a valuable biological indicator for risk assessment, prevention, and treatment of patients with breast cancer.

Effects of Candidalysin Derived from Candida albicans on the Expression of Pro-Inflammatory Mediators in Human Gingival Fibroblasts.

Candida albicans (Ca) is frequently detected in the peri-implant sulcus with peri-implantitis, a major postoperative complication after oral implant therapy. However, the involvement of Ca in the pathogenesis of peri-implantitis remains unclear. In this study, we aimed to clarify Ca prevalence in the peri-implant sulcus and investigated the effects of candidalysin (Clys), a toxin produced by Ca, on human gingival fibroblasts (HGFs). Peri-implant crevicular fluid (PICF) was cultured using CHROMagar and Ca colonization rate and colony numbers were calculated. The levels of interleukin (IL)-1ß and soluble IL-6 receptor (sIL-6R) in PICF were quantified by enzyme-linked immunosorbent assay (ELISA). Pro-inflammatory mediator production and intracellular signaling pathway (MAPK) activation in HGFs were measured by ELISA and Western blotting, respectively. The Ca colonization rate and the average number of colonies in the peri-implantitis group tended to be higher than those in the healthy group. IL-1ß and sIL-6R levels in the PICF were significantly higher in the peri-implantitis group than in the healthy group. Clys significantly induced IL-6 and pro-matrix metalloproteinase (MMP)-1 productions in HGFs, and co-stimulation with Clys and sIL-6R increased IL-6, pro-MMP-1, and IL-8 production levels in HGFs compared with Clys stimulation alone. These findings suggest that Clys from Ca plays a role in the pathogenesis of peri-implantitis by inducing pro-inflammatory mediators.

EZH2 promotes angiogenesis in peritoneal dialysis by epigenetically activating SP4 expression in the IL-6/sIL-6R signalling pathway.

Background: Interleukin-6 (IL-6)/soluble IL-6 receptor (sIL-6R) promotes peritoneal angiogenesis by stimulating SP4-mediated vascular endothelial growth factor (VEGF) production in peritoneal dialysis (PD). Moreover, histone methyltransferase enhancer of zeste homologue 2 (EZH2) is involved in IL-6/sIL-6R signalling via the acceleration of vascular endothelial growth factor (VEGF)-induced angiogenesis. However, the molecular mechanism underlying how EZH2 epigenetically activates VFGF expression in IL-6/sIL-6R signalling during PD is still unclear. Methods and Results: In this study, we measured the expression of EZH2, DNMT3B and SP4 in human peritoneal mesothelial cells (HPMCs) treated with IL-6/sIL-6R stimulation and/or EZH2 overexpression, silencing or inhibition. Methylation of the CpG site in the SP4 promoter region and VEGF production were measured under these treatments in HPMCs. Moreover, tube formation in human umbilical vein endothelial cells (HUVECs) was detected following treatment with conditioned media from these stimulated HPMCs. The 5/6 nephrectomy (5/6Nx) rat model was established, and the rats were injected with peritoneal dialysate. EZH2, DNMT3B and SP4 expression and microvessels were analysed in 5/6Nx + PD rats treated with IL-6/sIL-6R and EZH2 overexpression. The results showed that IL-6/sIL-6R and EZH2 overexpression enhanced the expression of EZH2, DNMT3B and SP4, but EZH2 silencing/inhibition reduced these expression levels. The results for VEGF production and tube formation in vitro followed the same trend. IL-6/sIL-6R and EZH2 overexpression increased the methylation percentage of the -170 bp CpG site in the SP4 promoter region in HPMCs. Moreover, IL-6/sIL-6R and EZH2 overexpression stimulated EZH2, DNMT3B and SP4 expression and promoted angiogenesis in 5/6Nx + PD rats. Conclusions: Thus, this study indicated that EZH2 is involved in IL-6/sIL-6R signalling and epigenetically regulates SP4 expression, thereby stimulating VEGF production and angiogenesis in PD. Targeting EZH2 is expected to be a novel therapeutic approach for end-stage renal disease (ESRD) patients with PD treatment.

IL-6 signaling in acute exercise and chronic training: Potential consequences for health and athletic performance.

The cytokine interleukin-6 (IL-6) is involved in a diverse set of physiological processes. Traditionally, IL-6 has been thought of in terms of its inflammatory actions during the acute phase response and in chronic conditions such as rheumatoid arthritis and obesity. However, IL-6 is also an important signaling molecule during exercise, being acutely released from working muscle fibers with increased exercise duration, intensity, and muscle glycogen depletion. In this context, IL-6 enables muscle-organ crosstalk, facilitating a coordinated response to help maintain muscle energy homeostasis, while also having anti-inflammatory actions. The range of actions of IL-6 can be explained by its dichotomous signaling pathways. Classical signaling involves IL-6 binding to a cell-surface receptor (mbIL-6R; present on only a small number of cell types) and is the predominant signaling mechanism during exercise. Trans-signaling involves IL-6 binding to a soluble version of its receptor (sIL-6R), with the resulting complex having a much greater half-life and the ability to signal in all cell types. Trans-signaling drives the inflammatory actions of IL-6 and is the predominant pathway in disease. A single nucleotide polymorphism (rs2228145) on the IL-6R gene can modify the classical/trans-signaling balance through increasing the levels of sIL-6R. This SNP has clinical significance, having been linked to inflammatory conditions such as rheumatoid arthritis and type 1 diabetes, as well as to the severity of symptoms experienced with COVID-19. This review will describe how acute exercise, chronic training and the rs2228145 SNP can modify the IL-6 signaling pathway and the consequent implications for health and athletic performance.

In vivo immunomodulation of IL6 signaling in a murine multiple trauma model.

A significant number of trauma patients die during the ICU phase of care because of a severe immune response. Interleukin-6 (IL6) plays a central role within that immune response, signaling through a membrane-bound (IL6-R) and a soluble IL6 receptor (sIL6-R). IL6 and the sIL6-R can form an agonistic IL6/sIL6-R-complex, activating numerous cells that are usually not IL6 responsive, a process called trans-signaling. We attempted to demonstrate that modulation of the IL6 signaling (classic signaling and trans-signaling) can attenuate the devastating immune response after trauma in a murine multiple trauma model. Mice were allocated to three study arms: sham, fracture or polytrauma. Half of the animals had the application of an IL6-R antibody following an intervention. After a pre-set time, blood samples were analysed for IL6 and sIL6-R serum levels, organs were analysed for neutrophil infiltration and end organ damage was evaluated. IL6 and sIL6-R showed a rapid peak after fracture, and much more markedly after polytrauma. These parameters were reduced significantly by globally blocking IL6 signaling via IL6-R antibody (Mab) application. Shock organ analysis also illustrated significant neutrophil infiltration following polytrauma, which was also abated via IL6-R Mab application. Furthermore, end organ damage was reduced by IL6-R Mab application. The study results prove the regulatory role of IL6 signaling pathways in polytrauma, with haemorrhagic shock being a major trigger of inflammatory response. Modulation of IL6 signaling shows promise in the prevention of adverse events like organ failure following major trauma and might be a target for in vivo immunomodulation to reduce mortality in severely injured patients, but further evaluation regarding classic IL6 signaling and IL6 trans-signaling is needed.

Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors.

Introduction: Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130), in the plasma have not been elucidated. Methods: Blood was collected from 106 patients with NSCLC before initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Plasma levels of IL-6, sIL-6R, sgp130, and their complexes were assessed by Cox regression hazard model to evaluate their clinical significance. The clinical role of IL-6 or IL-6R genetic polymorphisms was also analyzed. Results: Cox regression analysis showed that higher plasma IL-6 levels significantly predicted unfavorable overall survival (OS; hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.05-1.68, p = 0.012) in NSCLC patients treated with ICIs. However, plasma sIL-6R and sgp130 levels showed no prognostic significance (p = 0.882 and p = 0.934, respectively). In addition, the estimated concentrations of binary IL-6:sIL-6R and ternary IL-6:sIL-6R:sgp130 complexes and their ratios (binary/ternary complex) were not significantly associated with OS (p = 0.647, p = 0.727, and p = 0.273, respectively). Furthermore, the genetic polymorphisms of IL-6 (-634G>C) and IL-6R (48892A>C) showed no clinical role by Kaplan-Meier survival analysis (p = 0.908 and p = 0.639, respectively). Discussion: These findings demonstrated the clinical significance of plasma levels of IL-6, but not of other IL-6 signaling components, sIL-6R and sgp130, suggesting that classical IL-6 signaling, but not trans-signaling, may be related to anti-tumor immune responses in cancer patients treated with ICIs.

Increased TNF-α production in response to IL-6 in patients with systemic inflammation without infection.

Acute systemic inflammation can lead to life-threatening organ dysfunction. In patients with sepsis, systemic inflammation is triggered in response to infection, but in other patients, a systemic inflammatory response syndrome (SIRS) is triggered by non-infectious events. IL-6 is a major mediator of inflammation, including systemic inflammatory responses. In homeostatic conditions, when IL-6 engages its membrane-bound receptor on myeloid cells, it promotes pro-inflammatory cytokine production, phagocytosis, and cell migration. However, under non-physiologic conditions, such as SIRS and sepsis, leucocyte dysfunction could modify the response of these cells to IL-6. So, our aim was to evaluate the response to IL-6 of monocytes from patients diagnosed with SIRS or sepsis. We observed that monocytes from patients with SIRS, but not from patients with sepsis, produced significantly more TNF-α than monocytes from healthy volunteers, after stimulation with IL-6. Monocytes from SIRS patients had a significantly increased baseline phosphorylation of the p65 subunit of NF-κB, with no differences in STAT3 phosphorylation or SOCS3 levels, compared with monocytes from septic patients, and this increased phosphorylation was maintained during the IL-6 activation. We found no significant differences in the expression levels of the membrane-bound IL-6 receptor, or the serum levels of IL-6, soluble IL-6 receptor, or soluble gp130, between patients with SIRS and patients with sepsis. Our results suggest that, during systemic inflammation in the absence of infection, IL-6 promotes TNF-α production by activating NF-κB, and not the canonical STAT3 pathway.

IL-6 promotes low concentration of RANKL-induced osteoclastic differentiation by mouse BMMs through trans-signaling pathway.

The exact role of IL-6 in inflammatory osteoclast formation is still under debate. Our previous study demonstrated that IL-6 in the combination of sIL-6R significantly promoted low level of RANKL-induced osteoclast differentiation which was not affected by IL-6 alone. However, the precise molecular mechanisms underlying the regulation of sIL-6R-induced trans-signaling on osteoclast differentiation remains to be elucidated. Mouse bone marrow­derived monocytes (BMMs) were isolated and cultured with RANKL and IL-6/sIL-6R in the presence or absence of sgp130. TRAP staining and pit formation assay were used to visualize multinucleated giant osteoclasts and evaluate their bone resorption ability. Western blot and real time-PCR were applied to determine the activations of IL-6 signaling pathway and osteoclastogenesis- associated signaling pathways. The results showed that sIL-6R activation of IL-6 trans-signaling enhanced IL-6 signaling cascades and promoted low concentration of RANKL-induced osteoclasts formation and bone resorption by mouse BMMs. Furthermore, blocking IL-6 trans-signaling with sgp130 abrogated this promotive effect by suppressing NF-κB and JNK signaling pathways. In conclusion, sIL-6R-mediated trans-signaling pathway plays a decisive role in promotion of low level of RANKL-induced osteoclastic differentiation by IL-6/sIL-6R and targeting the IL-6 trans-signaling pathway may represent a potential strategy for inflammatory diseases with pathological bone resorption.

Identification of IL-6 Signalling Components as Predictors of Severity and Outcome in COVID-19.

IL-6 is one of the major mediators of the hyper-inflammatory responses with complex biological functions as it can signal via different modes of action. IL-6 by classical signalling has anti-inflammatory and antibacterial activities, while trans-signalling mediates pro-inflammatory effects. The net biological effect of IL-6 is established by multiple factors beyond its absolute concentration. Here, we assess the relationship between IL-6 signalling variables [IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130)] and outcomes in a cohort of 366 COVID-19 patients. The potential trans-signalling was evaluated by a ratio between the pro-inflammatory binary IL-6:sIL-6R complex and the inactive ternary IL-6:sIL-6R:sgp130 complex (binary/ternary complex) and the fold molar excess of sgp130 over sIL-6R (FME). Our data provide new evidence that high levels of IL-6, sIL-6R, sgp130, binary/ternary complex ratio, and low FME are independent predictors of COVID-19 severity in survivor patients (without death), and the combination of IL-6 + sIL-6R + sgp130 exhibited the most robust classification capacity. Conversely, in a subgroup of patients with a very poor prognosis, we found that high levels of IL-6 and low levels of sIL-6R, sgp130, and binary/ternary complex ratio were predictors of death. In this context, the highest predictive capacity corresponded to the combined analysis of IL-6 + FME + lymphopenia + creatinine. Herein, we present IL-6 signalling variables as a helpful tool for the early identification and stratification of patients with clear implications for treatment and clinical decision-making.

Research on the mechanism of berberine in the treatment of COVID-19 pneumonia pulmonary fibrosis using network pharmacology and molecular docking.

Purpose Pulmonary fibrosis caused by COVID-19 pneumonia is a serious complication of COVID-19 infection, there is a lack of effective treatment methods clinically. This article explored the mechanism of action of berberine in the treatment of COVID-19 (Corona Virus Disease 2019, COVID-19) pneumonia pulmonary fibrosis with the help of the network pharmacology and molecular docking. Methods We predicted the role of berberine protein targets with the Pharmmapper database and the 3D structure of berberine in the Pubchem database. And GeneCards database was used in order to search disease target genes and screen common target genes. Then we used STRING web to construct PPI interaction network of common target protein. The common target genes were analyzed by GO and KEGG by DAVID database. The disease-core target gene-drug network was established and molecular docking was used for prediction. We also analyzed the binding free energy and simulates molecular dynamics of complexes. Results Berberine had 250 gene targets, COVID-19 pneumonia pulmonary fibrosis had 191 gene targets, the intersection of which was 23 in common gene targets. Molecular docking showed that berberine was associated with CCl2, IL-6, STAT3 and TNF-α. GO and KEGG analysis reveals that berberine mainly plays a vital role by the signaling pathways of influenza, inflammation and immune response. Conclusion Berberine acts on TNF-α, STAT3, IL-6, CCL2 and other targets to inhibit inflammation and the activation of fibrocytes to achieve the purpose of treating COVID-19 pneumonia pulmonary fibrosis.

Genetic Associations Between IL-6 and the Development of Autoimmune Arthritis Are Gender-Specific.

Objectives: To find out the genetic association between IL6 and autoimmune arthritis. Methods: We performed a two-sample Mendelian randomization (MR) study using multiple genome-wide association studies (GWAS) datasets. Furthermore, a sex-stratified MR study was performed to identify sexual dimorphism in the association between IL6 and autoimmune arthritis. Then, LocusZoom plots were displayed based on the IL6R gene region to present evidence of genetic colocalization between diseases. Results: The MR result denoted a genetic association between the increased level of IL-6 signaling and risk of RA (ß=0.325, 95%CI 0.088, 0.561, p=7.08E-03) and AS (ß=1.240, 95%CI 0.495, 1.980, p=1.1E-03). Accordingly, sIL6R was found to have negatively correlation with the onset of RA (ß=-0.020, 95%CI -0.0320, -0.008, p=1.18E-03) and AS (ß=-0.125, 95%CI -0.177, -0.073, p=2.29E-06). However, no genetic association between IL6/sIL6R and PsA was detected. The gender-stratified MR analysis showed that IL6 was associated with AS in the male population, with RA in the female population, and with PsA in the male population. Additionally, ADAR, a gene identified by a sensitive test, could be the reason for the nonsignificant association between IL6 and PsA in a pooled population. Conclusion: Our findings showed that the overactive IL6 signal pathway led to autoimmune arthritis, especially in RA and AS. Sexual difference was also observed in IL6-intermediate susceptibility to autoimmune arthritis.

Selective Interleukin-6 Trans-Signaling Blockade Is More Effective Than Panantagonism in Reperfused Myocardial Infarction.

Interleukin (IL)-6 is an emerging therapeutic target in myocardial infarction (MI). IL-6 has 2 distinct signaling pathways: trans-signaling, which mediates inflammation, and classic signaling, which also has anti-inflammatory effects. The novel recombinant fusion protein sgp130Fc achieves exclusive trans-signaling blockade, whereas anti-IL-6 antibodies (Abs) result in panantagonism. In a rat model of reperfused MI, sgp130Fc, but not anti-IL-6-Ab, attenuated neutrophil and macrophage infiltration into the myocardium, reduced infarct size, and preserved cardiac function 28 days after MI. These data demonstrate the efficacy of exclusive IL-6 trans-signaling blockade and support further investigation of sgp130Fc as a potential novel therapy in MI.

Depression and interleukin-6 signaling: A Mendelian Randomization study.

BACKGROUND: A large body of research has reported associations between depression and elevated interleukin-6 (IL-6), a cytokine with several roles including pro-inflammatory signaling. The nature and directionality of this relationship are not yet clear. In this study we use Mendelian Randomization to examine the possibility of a causal relationship between IL-6 and depressive symptoms, and to explore multiple signaling pathways that could serve as mechanisms for this relationship. METHODS: This study uses a two-sample Mendelian Randomization design. Data come from the UK Biobank (n = 89,119) and published summary statistics from six existing GWAS analyses. The primary analysis focuses on the soluble interleukin-6 receptor (sIL-6R), which is involved in multiple signaling pathways. Exploratory analyses use C-reactive protein (CRP) and soluble glycoprotein 130 (sgp130) to further examine potential underlying mechanisms. RESULTS: Results are consistent with a causal effect of sIL-6R on depression (PCA-IVW Odds Ratio: 1.023 (95% Confidence Interval: 1.006-1.039), p = 0.006). Exploratory analyses demonstrate that the relationship could be consistent with either decreased classical signaling or increased trans signaling as the underlying mechanism. DISCUSSION: These results strengthen the body evidence implicating IL-6 signaling in depression. When compared with existing observational and animal findings, the direction of these results suggests involvement of IL-6 trans signaling. Further study is needed to examine whether IL6R genetic variants might influence IL-6 trans signaling in the brain, as well as to explore other potential pathways linking depression and inflammation.