Search

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can induce mild to life-threatening symptoms. Especially individuals over 60 years of age or with underlying comorbidities, including heart or lung disease and diabetes, or immunocompromised patients are at a higher risk. Fatal multiorgan damage in coronavirus disease 2019 (COVID-19) patients can be attributed to an interleukin-6 (IL-6)-dominated cytokine storm. Consequently, IL-6 receptor (IL-6R) monoclonal antibody treatment for severe COVID-19 cases has been approved for therapy. High concentrations of soluble IL-6R (sIL-6R) were found in COVID-19 intensive care unit patients, suggesting the involvement of IL-6 trans-signaling in disease pathology. Here, in analogy to bispecific antibodies (bsAbs), we developed the first bispecific IL-6 trans-signaling inhibitor, c19s130Fc, which blocks viral infection and IL-6 trans-signaling. c19s130Fc is a designer protein of the IL-6 trans-signaling inhibitor cs130 fused to a single-domain nanobody directed against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. c19s130Fc binds with high affinity to IL-6:sIL-6R complexes as well as the spike protein of SARS-CoV-2, as shown by surface plasmon resonance. Using cell-based assays, we demonstrate that c19s130Fc blocks IL-6 trans-signaling-induced proliferation and STAT3 phosphorylation in Ba/F3-gp130 cells as well as SARS-CoV-2 infection and STAT3 phosphorylation in Vero cells. Taken together, c19s130Fc represents a new class of bispecific inhibitors consisting of a soluble cytokine receptor fused to antiviral nanobodies and principally demonstrates the multifunctionalization of trans-signaling inhibitors. IMPORTANCE The availability of effective SARS-CoV-2 vaccines is a large step forward in managing the pandemic situation. In addition, therapeutic options, e.g., monoclonal antibodies to prevent viral cell entry and anti-inflammatory therapies, including glucocorticoid treatment, are currently developed or in clinical use to treat already infected patients. Here, we report a novel dual-specificity inhibitor to simultaneously target SARS-CoV-2 infection and virus-induced hyperinflammation. This was achieved by fusing an inhibitor of viral cell entry with a molecule blocking IL-6, a key mediator of SARSCoV-2-induced hyperinflammation. Through this dual action, this molecule may have the potential to efficiently ameliorate symptoms of COVID-19 in infected individuals. [ABSTRACT FROM AUTHOR]

Increased neutrophil–endothelial binding and inflammatory responses are significant pathophysiological events in the maternal vascular system in preeclampsia, a hypertensive disorder in human pregnancy. Interleukin 6 (IL-6) and its soluble receptors (soluble IL-6R (sIL-6R) and soluble gp130 (sgp130)) are critical inflammatory mediators. During pregnancy, maternal IL-6 and sgp130 levels were increased, but sIL-6R levels were decreased, in women with preeclampsia compared to normotensive pregnant women. However, little is known about differences in IL-6, sIL-6R, and sgp130 production by neutrophils and endothelial cells between normal pregnancy and preeclampsia. To study this, we isolated neutrophils and cultured human umbilical vein endothelial cells (HUVECs) from normal and preeclamptic pregnancies. Production of IL-6, sIL-6R, and sgp130 was measured. The role of placental factor(s)-mediated neutrophil production of IL-6, sIL-6R, and sgp130 was also determined by pretreating neutrophils with placental conditioned medium generated from placental villous cultures. We found that IL-6 and sgp130 were mainly produced by endothelial cells, while sIL-6R was mainly produced by neutrophils. Endothelial cells from preeclampsia produced significantly more IL-6 and sgp130, and neutrophils from preeclampsia produced significantly less sIL-6R than normal pregnancy cells. Interestingly, production of IL-6, sIL-6R, and sgp130 were time-dependently increased when neutrophils and endothelial cells were co-cultured. We also found that neutrophils from normal pregnancies produced more IL-6, but less sIL-6R, after being primed by preeclamptic-placental conditioned medium. These results demonstrated that neutrophils and endothelial cells have different capacities in producing IL-6, sIL-6R, and sgp130 between normal pregnancy and preeclampsia. These results also provide evidence that the placenta plays a role in inducing neutrophil activation in preeclampsia. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of reduced glutathione and ulinastatin on the expressions of interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R), and soluble glycoprotein 130 (sgp130) in peripheral blood of paraquat-poisoned patients. Methods: In this retrospective study, 88 patients with paraquat poisoning admitted to Dongying People's Hospital, Dongying, China from February 2017 to October 2020 were divided into control group (n = 40) and study group (n = 48), based on treatment type. The control group received conventional treatments, while the study group was given reduced glutathione in combination with ulinastatin. Treatment efficacy and peripheral blood expression levels were compared. Results: Compared to the control group, curative effect was significantly higher in the study group (p < 0.05). The expression levels of IL-6, sIL-6R, and sgp130 in the peripheral blood at the early, middle and late periods in the study group were markedly lower. The number of patients with flake-like or dotted opacity, increased lung texture, pleural effusion and ground glass opacity in the study group during the early period was lower (p < 0.05). Moreover, the number of patients with pulmonary edema, fibrous cord, pleural effusion, ground glass opacity and reticular opacity during the middle period was markedly lower for the study group, while the population of patients with honeycomb lung, fibrous cord, nodules and reticular opacity in the study group was higher t (p < 0.05). Conclusion: A combination of reduced glutathione and ulinastatin produces significant therapeutic effect on paraquat poisoning by down-regulating the serum expressions of IL-6, sIL-6 and sgp130, inhibiting inflammation, and mitigating pulmonary lesions. [ABSTRACT FROM AUTHOR]

Abstract Vascular inflammation plays a critical role in the pathogenesis of diabetic retinopathy. Recently, Interleukin-6 (IL-6) trans-signaling via soluble IL-6 receptor (sIL-6R) has emerged as a prominent regulator of inflammation in endothelial cells. This study was designed to test the hypothesis that selective inhibition of the IL-6 trans-signaling pathway will attenuate inflammation and subsequent barrier disruption in retinal endothelial cells. Human retinal endothelial cells (HRECs) were exposed to IL-6 and sIL-6R to induce IL-6 trans-signaling and the commercially available compound sgp130Fc (soluble gp-130 fused chimera) was used to selectively inhibit IL-6 trans-signaling. IL-6 trans-signaling activation caused a significant increase in STAT3 phosphorylation, expression of adhesion molecules, ROS production and apoptosis in HRECs whereas a significant decrease in mitochondrial membrane potential and NO production was observed in IL-6 trans-signaling activated cells. These changes were not observed in cells pre-treated with sgp130Fc. IL-6 trans-signaling activation was sufficient to cause barrier disruption in endothelial monolayers and pre-treatment of HRECs with sgp130Fc, maintained endothelial barrier function similar to that of untreated cells. Thus, in conclusion, these results indicate that IL-6 trans-signaling is an important mediator of inflammation, apoptosis and barrier disruptive effects in the retinal endothelial cells and inhibition of the IL-6 trans-signaling pathway using sgp130-Fc attenuates vascular inflammation and endothelial barrier disruption. Highlights • IL-6 trans-signaling is an important mediator of inflammation and barrier disruption in the retinal endothelial cells. • An anti-inflammatory molecule, sgp130Fc selectively inhibits the IL-6 trans-signaling pathway. • sgp130Fc treatment attenuates IL-6 trans-signaling mediated inflammation and apoptosis in the retinal endothelial cells. [ABSTRACT FROM AUTHOR]

The aim of this study was to measure the impact, at 24 h postexercise, of a single exercise bout on plasma inflammatory markers such as calprotectin, IL-6, sIL-6 R, sgp130 and the hypothalamic-pituitary-adrenal (HPA) axis in children with juvenile idiopathic arthritis (JIA). Twelve children with JIA attended the laboratory on three consecutive days (control day, exercise day and 24 h post-exercise), including a 20-min exercise bout on a cycle-ergometer at 70 % of max. HR at 8:30 a.m. on day 2. Plasma concentrations of calprotectin, IL-6, sIL-6 R, sgp130, cortisol, ACTH and DHEA were measured on venous blood samples taken every day.at rest and at 8:30, 8:50, 9:30, 10:30 a.m. and 12:00, 3:00, 5:30 p.m. A single exercise bout increased plasma calprotectin 1.7-fold (p < 0.001) but did not increase IL-6 and soluble IL-6 receptors in short-term post-exercise recovery. However, at 24 h post-exercise, calprotectin, IL-6 and its receptors had decreased compared to control-day levels. There was a transient 2-fold increase in post-exercise self-evaluated pain (p = 0.03) that disappeared in the evening without repercussions the following day. Physical activity in children with JIA results in a slight transient systemic inflammation but seems to be followed by counter-regulation at 24 h post-exercise with a decrease in proinflammatory markers. [ABSTRACT FROM AUTHOR]

Background and aims Inflammation and endocrine disorders are considered as major pathogenic factors of coronary atherosclerotic disease (CAD). Sgp130, a natural antagonist of IL-6 trans -signaling, and sex hormones, especially testosterone and estradiol, are prominently considered as anti-atherosclerotic. The aim of this study was to investigate the possible association between serum sgp130 and testosterone and estradiol in male CAD patients. Methods A total of 254 male patients with CAD and 122 male controls were recruited for this study. Circulating IL-6, sIL-6, sgp130 were measured by an enzyme-linked immunosorbent assay. Serum concentrations of hs-CRP, testosterone, estradiol, and other routine biochemical markers were also quantified. Besides, we observed the effects of testosterone and estradiol on sgp130 in HUVECs. Results Serum levels of sgp130, testosterone and estradiol and the ratio of testosterone and estradiol (T/E2) were obviously decreased in CAD patients compared with controls. Pearson correlation analysis showed that serum sgp130 levels had positive correlations with testosterone ( r = 0.295, p < 0.001) and estradiol ( r = 0.338, p < 0.001) levels in CAD patients. In addition, multiple regression analysis indicated that serum sgp130 was positively associated with estradiol ( β -coefficient = 0.450, p < 0.001) and T/E2 ratio ( β -coefficient = 0.257, p = 0.001). Furthermore, basic studies found that supernatant sgp130 levels of HUVECs were significantly increased by the cooperativity of testosterone and estradiol. Conclusions Low levels of serum sgp130 were positively associated with sex hormones in male patients with CAD, suggesting an important role of sgp130 in the presence of low and imbalanced sex hormones levels. Thus, regulation of sgp130 levels by rebalancing sex hormones has the potential to be a novel therapeutic for the treatment of CAD. [ABSTRACT FROM AUTHOR]

We identified and validated several novel inflammatory markers of cognitive performance in community-living older persons. An exploratory study (n = 83) correlated 177 inflammatory markers assayed by Luminex with the Mini–Mental State Examination (MMSE) and identified 8 inflammatory markers for enzyme-linked immunosorbent assay (ELISA) and correlations with MMSE, Montreal Cognitive Assessment (MoCA), and cognitive impairment in the validation study (n = 139). The validation study replicated the significant associations of soluble interleukin-2 receptor alpha chain (sIL-2Rα; p = 0.050), soluble tumor necrosis factor receptor 2 (sTNFR2; p = 0.002) and soluble glycoprotein 130 (sgp130; p = 0.026) with MMSE, and sIL-2Rα ( p = 0.019) and sgp130 ( p < 0.001) with MoCA. Significant trends of associations of tertiles of sgp130, sIL-2Rα, and sTNFR2 were found with cognitive impairment. Highly elevated estimates of association of high versus low tertiles were obtained for sgp130 (odds ratio [OR] = 4.24, 95% confidence interval [CI] 0.96–18.8), sIL-2Rα (OR = 3.94, 95% CI 0.83–18.7), and sTNFR2 (OR = 7.58, 95% CI 1.19–48.1). sgp130, sTNFR2, and sIL-2Rα are promising inflammatory markers of low cognitive performance for further investigation. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) signaling can be divided into classic signaling (via the membrane-bound IL-6 receptor, IL-6R) and trans-signaling (via the soluble IL-6R, sIL-6R), and both modes of signaling activate cells via a homodimer of the ubiquitously expressed β-receptor glycoprotein 130 (gp130). IL-6 trans-signaling is responsible for most of the pro-inflammatory activities of IL-6 and plays a role in many inflammatory diseases including inflammation-driven cancers. IL-6 trans-signaling can be selectively inhibited by soluble forms of gp130. To date, three forms of sgp130 (full-length sgp130, sgp130-RAPS and sgp130-E10) with different molecular weight have been described, which originate from alternative splicing or alternative polyadenylation of the gp130 mRNA. All these proteins are capable of blocking signaling of the IL-6/sIL-6R complex, albeit with different efficacy. The full length form of sgp130 comprises the domains D1 to D6 and a short unique C-terminus which arises from alternative splicing. In the present study, we analyze the role of a unique cysteine residue (Cys-628) within this C-terminus, which is contained neither in the membrane-bound gp130 nor in the two other sgp130 forms. Full-length sgp130 can form a disulfide-linked dimer via this cysteine residue. These natural sgp130 dimers are absent under reducing conditions or in a sgp130 C628A mutant. Although the disulfide-dimerized sgp130 represents only a small fraction of the total amount of sgp130 and, thus, may appear to be dispensable for the global inhibitory activities of sgp130 in the circulation, it may represent a further possibility to modulate gradients of sgp130 with different properties depending on the local redox potential in a cell- or tissue-dependent manner. [ABSTRACT FROM AUTHOR]

Soluble receptor of IL-6 (sIL-6R) and antagonist of the receptor complex, soluble glycoprotein 130 (sgp130) mediate opposite effects during inflammation. We measured the levels of these cytokines and their ratio in rat blood on the model of acute lung injury. The injury was modeled by the intratracheal administration of LPS. The levels of sgp130 and sIL-6R increased during the inflammatory process in the injured lungs. The sgp130/sIL-6R ratio increased or decreased depending on the intensity of the inflammatory process. sgp130/sIL-6R ratio might reflect the intensity of inflammation during lung injury. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) is a multifunctional cytokine with well-defined pro- and anti-inflammatory properties. Although only small amounts in the picogram range can be detected in healthy humans, IL-6 expression is highly and transiently up-regulated in nearly all pathophysiological states. IL-6 induces intracellular signaling pathways after binding to its membrane-bound receptor (IL-6R), which is only expressed on hepatocytes and certain subpopulations of leukocytes (classic signaling). Transduction of the signal is mediated by the membrane-bound β-receptor glycoprotein 130 (gp130). In a second pathway, named trans-signaling, IL-6 binds to soluble forms of the IL-6R (sIL-6R), and this agonistic IL-6/sIL-6R complexes can in principle activate all cells due to the uniform expression of gp130. Importantly, several soluble forms of gp130 (sgp130) are found in the human blood, which are considered to be the natural inhibitors of IL-6 trans-signaling. Most pro-inflammatory roles of IL-6 have been attributed to the trans-signaling pathway, whereas anti-inflammatory and regenerative signaling, including the anti-bacterial acute phase response of the liver, is mediated by IL-6 classic signaling. In this simplistic view, only a minority of cell types expresses the IL-6R and is therefore responsive for IL-6 classic signaling, whereas gp130 is ubiquitously expressed throughout the human body. However, several reports point towards a much more complex situation. A plethora of factors, including proteases, cytokines, chemical drugs, and intracellular signaling pathways, are able to modulate the cellular expression of the membrane-bound and soluble forms of IL-6R and gp130. In this review, we summarize current knowledge of regulatory mechanisms that control and regulate the dynamic expression of IL-6 and its two receptors. [ABSTRACT FROM AUTHOR]

Background & Aims: Interleukin-6 (IL-6) is a crucial factor in liver regeneration following partial hepatectomy (PH); however, the role of IL-6 and IL-6 trans-signaling in particular, in hepatocyte mitosis remains controversial. IL-6 trans-signaling relies upon the release of the soluble IL-6R (sIL-6R), which binds IL-6 to form an agonistic IL-6/sIL-6R complex. Herein we have examined the hypothesis that IL-6 trans-signaling plays a crucial and distinct role in liver regeneration following PH. Methods: The specific IL-6/sIL-6R antagonist, sgp130Fc, was expressed in mice and analyzed for its effect on hepatocyte mitosis following PH. Alternatively, we examined the effect of the IL-6/sIL-6R super-agonist, Hyper-IL-6, or IL-6 expressed either alone or in combination with hepatocyte growth factor (HGF) on hepatocyte mitosis in the absence of PH. Results: Following PH, the dramatic rise of circulating IL-6 levels is accompanied by a concurrent ∼2-fold increase in circulating sIL-6R levels. Ectopic expression of sgp130Fc reduced hepatocyte mitosis by about 40% at early times following PH, while substantially reducing AKT, but not STAT3, activation. But, ectopic Hyper-IL-6 expression in mice without PH was not mitogenic to hepatocytes in vivo. Rather, Hyper-IL-6, but not IL-6, markedly increased HGF-induced hepatocyte mitosis. This cooperative effect correlated with greater resistance of HIL-6 than IL-6 to HGF-mediated reduction of AKT activation, rather than changes in STAT3 or MAPK signaling, and was completely blocked by PI3K inhibition. Conclusions: Following PH, IL-6/sIL-6R cooperates with growth factors, through a PI3K/AKT-dependent mechanism to promote entry of hepatocytes into the cell cycle. [Copyright &y& Elsevier]

Abstract: Objective: Increased interleukin-6 plasma levels have been reported in metabolic syndrome (MS); nevertheless, it is unclear whether interleukin-6 activity is exerted through direct signalling only or also through the “trans-signalling”. This issue is important to clarify since signalling and “trans-signalling” affect different tissues. We investigated the relationship between MS and the interleukin-6 system in an older population. Methods: Data from 997 older community dwelling individuals (age≥65 years; females: 56.2%) enrolled the InChianti study were analysed. Interleukin-6, soluble interleukin-6 receptor (sIL-6r), and soluble glycoprotein 130 (sgp130) were measured on plasma by ELISA. MS was defined by the NCEP ATP III criteria; 309 individuals (31%) resulted affected by MS. Results: Subjects with MS had higher interleukin-6 and sgp130 levels compared to controls; a trend toward higher levels of sIL-6R was also observed. The risk of having MS was increased in individuals with high sIL-6r or/and sgp130 levels, independent of age, gender, and interleukin-6 levels. Elevated sgp130 levels were associated with higher plasma glucose, HOMA, triglycerides, and with diabetes both in subjects with and without MS. Although the risk of high sgp130 levels was generally associated with MS (O.R.: 1.77, 95%C.I.: 1.39–2.25), this excess of risk was not present in MS phenotypes excluding the criteria “elevated glucose” or “elevated triglycerides”. Furthermore, the association between sgp130 and MS disappeared after adjustment for HOMA. Conclusions: We found that older individuals with MS have increased sgp130 plasma levels compared with controls; nevertheless, our data suggest that this association might be mediated by insulin resistance. [Copyright &y& Elsevier]

In chronic liver disease, high circulating interleukin (IL)-6 contrasts with a poor acute phase response. We evaluated the impact of liver and circulating IL-6-receptor (IL-6R) forms on IL-6 bioactivity in chronic liver disease. IL-6, soluble IL-6-receptor and sgp130 levels were assayed in plasma from 45 patients with alcoholic liver disease, 84 with hepatitis C virus (HCV) infection undergoing transjugular liver biopsies and 15 healthy subjects. IL-6R mRNA was quantified on liver extracts from 54 patients with alcoholic liver disease with or without cirrhosis and 18 HCV-infected patients. The effect of gp130–Fc on fibrinogen secretion induced by IL-6 trans-signalling was evaluated on hepatocyte cultures. Levels of plasma IL-6 and sgp130, but not soluble IL-6R, increased with the stage of chronic liver disease, and correlated significantly with disease severity. Alcoholic liver disease patients had higher plasma IL-6 levels than hepatitis C, but lower liver IL-6R expression. In alcoholic and HCV-related liver diseases, liver IL-6R expression decreased with advanced fibrosis stage. In vitro, on hepatocytes, gp130–Fc blunted the acute phase response while soluble IL-6R enhanced IL-6 stimulation. In advanced chronic liver disease, high plasma IL-6 is associated with low liver IL-6R expression. This situation enables high plasma sgp130 to act as a major negative regulator of liver IL-6 trans-signalling, as demonstrated functionally here on hepatocytes. This might explain the poor acute phase response induced by IL-6 in chronic liver disease. [ABSTRACT FROM AUTHOR]

Tocilizumab, humanized anti-IL-6R antibody is a novel anti-rheumatic drug. In the present study, we examined the influence of tocilizumab on the inhibitory activity of soluble gp130 (sgp130) against IL-6 signaling. BAF-h130 cells, human gp130 transfected mouse pro-B cell line, were cultured with the mixture with IL-6, sIL-6R and sgp130 for 72 h. BAF-h130 cells proliferated by the addition of both IL-6 and sIL-6R, but not IL-6 or sIL-6R alone. The proliferation induced by IL-6/sIL-6R complex was inhibited by sgp130 concentration-dependently. Tocilizumab inhibited IL-6/sIL-6R-induced cell proliferation. On the other hand, it did not affect the suppressive property of sgp130. To examine if tocilizumab can dissociate IL-6/sIL-6R/sgp130 complex, we established an ELISA system to detect IL-6/sIL-6R/sgp130 complex using anti-IL-6R coated ELISA plate. The results clearly indicated that ELISA system established was detectable IL-6/sIL-6R/sgp130 complex in a concentration dependent manner. Tocilizumab was added to IL-6/sIL-6R/sgp130 complex-fixed plate and then remaining IL-6/sIL-6R/sgp130 complexes on the plate were measured. The amount of IL-6/sIL-6R/sgp130 complexes on the plate was not changed by the addition of tocilizumab. In conclusion, tocilizumab exerts its inhibitory effect through the inhibition of IL-6R directly without affecting natural inhibitor sgp130. [ABSTRACT FROM AUTHOR]

Abstract: Soluble gp130 is the natural inhibitor of trans-signaling mediated by the soluble IL-6/IL-6R complex. In mouse models, recombinant sgp130 has been successfully applied for the treatment of diseases that are triggered and maintained by soluble IL-6R like Crohn’s disease, peritonitis, rheumatoid arthritis, and colon cancer. The novel heterodimeric cytokine IL-27 (p28/EBV-induced gene 3) has been shown to act via a heterodimeric receptor complex of gp130 and the WSX-1 receptor, and to co-regulate the Th1 immune response after infection. Therefore, we have tested the potential of the recombinant sgp130-Fc protein to also inhibit signaling-mediated IL-27. Here we show that sgp130-Fc does not interfere with IL-27 signaling. We therefore conclude that IL-27 does not bind with high affinity to gp130. [Copyright &y& Elsevier]

Objective.—To investigate whether cytokines are altered during the active period of cluster headache. Background.—Patients with cluster headache show activation of the hypothalamus in PET studies and via endocrinologic parameters. Data also suggest an inflammatory process occurs in cluster headache. A connection between the presumed inflammatory cause, an immunological activation, and the hypothalamus could be generated by certain cytokines. Design and Methods.—ELISA was used to determine the serum levels of soluble interleukin-2 receptors, interleukin-1, interleukin-6, and 2 soluble interleukin-6 receptors (sIL-6R and soluble gp130) in 18 patients with cluster headache (6 women and 12 men) during the cluster period and in 17 healthy controls who were headache-free (3 women and 14 men). Results.—Patients with cluster headache had significantly increased soluble interleukin-2 receptors (413.6±223 U/mL vs. 290.0±112 U/mL; P < .05) compared with controls. Serum levels of interleukin-1 (0.29±0.30 pg/mL vs. 0.13±0.13 pg/mL, n.s.), interleukin-6 (0.87±0.6 pg/mL vs. 0.91±0.7 pg/ml; n.s.), soluble interleukin-6 receptors (33,131±8,349 pg/mL vs. 35,063±7,606 pg/mL; n.s.), or soluble gp130 (289±59 pg/mL vs. 283±20 pg/mL; n.s.) did not differ between the 2 groups, although patients with cluster tended to have higher interleukin-1 values. Conclusions.—Because elevated soluble interleukin-2 receptors indicate T cell activation, our findings suggest immune activation during cluster headache. Because interleukin-2 can activate the hypothalamus and stimulate the release of Corticotropin-releasing Factor (CRF), interleukin-2 could link a putative immunological cause of cluster headache with the observed hypothalamic activation. Systemic changes of interleukin-1 or the interleukin-6 system do not seem to play a role in cluster headache, as no alterations of serum levels were observed. Even so,... [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) can be involved in several diseases including lymphoid malignancies. This cytokine binds to soluble IL-6 receptor (sIL-6R) circulating in blood, leading to signal transduction via gp130. Soluble IL-6R shows agonistic activity for IL-6, and the soluble form of gp130 (sgp130) an antagonistic effect against the complex IL-6/sIL-6R. Viscum album extract (IscadorR) as an immunomodulator is used in the treatment of malignant disorders. In this study we investigated the effect of this treatment on the serum levels of IL-6, sIL-6R and sgp130 in B-cell lymphoma patients (n = 27), in comparison to healthy controls (n = 28). Twenty-one of 27 patients had been treated previously with chemo/radiotherapy. The patients were divided into two groups; those with short-term (investigated before and during treatment) or those with long-term Viscum album (VA) therapy (investigated during therapy). The serum levels of the three parameters were determined by ELISA.In patients having short-term treatment IL-6 values were similar to those of controls. During long-term therapy the values were significantly lower (P<0.05). The values of sIL-6R were elevated only in long-term treated patients (P<0.05), the values of sgp130 in both short-term (P<0.05) and in long-term treated patients (P=0.001). There is a significant correlation (P<0.05) between levels of sIL-6R and sgp130 in both therapy groups at 24 hours after injection. This indicates that the potent effect of sIL-6R on the biological activity of IL-6 could be inhibited by sgp130 as antagonist. Clinical data show that half of the patients (6/12) with long-term treatment had a continuous complete remission, whereas only 2/15 patients with short-term treatment had a complete remission. [Copyright &y& Elsevier]

Abstract: Cell adhesion molecules are cell surface glycoproteins that may act as mediators in the metastatic process. In this study we measured serum levels of the soluble intercellular adhesion molecule-1 (sICAM-1) in 74 patients with various tumours, divided into four groups according to tumour stage and previous therapy. Serum values of sgp130 were determined in the same patients. As controls we took healthy persons (n =18 for sICAM-1; n =28 for sgp130). Two parameters were determined by ELISA. The serum values of sICAM-1 were significantly elevated compared to controls in stages III + IV both without and after previous chemo/radiotherapy (P <0.05). In stages I + II without or with previous therapy there was no significance. The serum values of sgp130 were increased significantly at each tumour stage both without and after therapy. There were significant correlations between the values of sICAM-1 and sgp130 in patients with progression (tumour stage III + IV without therapy P <0.01; after chemo/radiotherapy P <0.05). To our knowledge this relationship between the two serum parameters has never before been reported. The simultaneous measurement of sICAM-1 and sgp130 could be important in the evaluation of the clinical progression of malignant diseases. [ 1 ] Tel.: +41 61 706 7261; fax: +41 61 706 7173. [Copyright &y& Elsevier]