European cytokine network最新文献

There is currently no safe or effective treatment for inflammatory bowel disease (IBD), which is defined as recurrent and persistent intestinal inflammation. Thymic stromal lymphopoietin (TSLP) has been shown to be associated with the pathogenesis of IBD, and the JAK2/STAT5 signalling pathway has demonstrated much promise as a novel therapeutic target for IBD. In this study, we first evaluated levels of TSLP in dextran sodium sulphate (DSS)-induced IBD mice. Second, we applied tezepelumab, an anti-TSLP monoclonal antibody (20 μg per mouse, intraperitoneally), to DSS-induced IBD mice and quantified the signs of histopathological change, intestinal inflammation, and integrity of the mucosal barrier. In addition, the effect of DSS and/or tezepelumab on the phosphorylation of the JAK/STAT pathway was investigated. TSLP expression levels were elevated in DSS-induced IBD mice, whereas TSLP antibody treatment suppressed the pathological features associated with IBD and alleviated intestinal inflammation and mucosal barrier disruption. Moreover, level of phosphorylated JAK2/STAT5 were increased in DSS-induced IBD mice, but were strongly decreased in the presence of tezepelumab. Our findings suggest that targeting TSLP via the JAK2/STAT5 signalling pathway may be an effective approach for the treatment of IBD.

Endometrial cancer (EC) is recognized as the second most common type of cancer among women. Interleukin-37 (IL-37) is a recently discovered member of the IL-1 cytokine family characterized by its anti-inflammatory properties, which are believed to have both anti-tumour and tumorigenic effects. However, the precise role of IL-37 in the development of EC remains largely unknown. In the current study, we aimed to explore genotype and allele frequencies of the IL-37 gene (rs4241122) and measure IL-37 protein levels in patients with EC, with a view to determining the clinical significance in these patients. A total of 105 patients with confirmed EC and 105 healthy controls, aged 31-73, participated in the study. IL-37 serum levels were investigated using an ELISA method, while the frequency of genotypes and alleles of the IL-37 gene was determined using the ARMS-PCR method. The findings demonstrate a significant increase in IL-37 serum levels in EC patients compared to controls (p<0.0001). Moreover, higher levels of IL-37 were strongly associated with unfavourable indices, such as EC grade III, poorly differentiated tumours, and regional spread of tumour cells (p<0.05). However, genotyping of the IL-37 gene revealed no significant difference between the two groups, and there was no association between IL-37 genotype and IL-37 protein level or clinicopathological characteristics (p>0.05). The results of this study suggest that elevated serum levels of may contribute to tumour progression, probably through its immune suppressive activity. Clinically, IL-37 may serve as a promising factor and/or therapeutic target for EC management, although, further studies are warranted.

Spermatogenesis is the complicated process of sperm generation. During this process, spermatogonial cells proliferate and differentiate via meiotic and post-meiotic stages to produce mature sperm. This process is under the regulation of testicular autocrine/paracrine factors. In addition, endocrine factors are crucial to complete spermatogenesis. We aimed to localize granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor (GM-CSFR) in testicular cells and further evaluate its involvement in the development of spermatogenesis in vitro. We isolated cells from seminiferous tubule cells of seven-day-old mice and cultured them in vitro using a methylcellulose culture system (MCS), in the presence of GM-CSF and/or testosterone for four weeks. The cells were then examined for markers of different stages of spermatogenesis by immunofluorescence staining and/or qPCR analyses. Our results revealed the presence of GM-CSF and GM-CSFR in testicular cells (premeiotic and meiotic cells as well as somatic cells; Leydig and Sertoli cells). We further demonstrated the development of colonies/spheroids in the MCS which contained pre-meiotic, meiotic, and post-meiotic cells. The addition of GM-CSF to the MCS significantly increased the percentage of pre-meiotic and meiotic cells compared to control. Furthermore, the addition of GM-CSF and testosterone together significantly increased the percentage of cells in the post-meiotic stage compared to the addition of each separately. In conclusion, our results indicate that testicular cells express GM-CSF/GM-CSFR, and that GM-CSF is involved in the development of different stages of spermatogenesis in vitro. Furthermore, testosterone enhances the development of spermatogenic cells and potentiates the effect of GMCSF on the development of post-meiotic cells. These findings provide evidence that GM-CSF and testosterone are involved in the development of spermatogenesis in vitro and in vivo. In brief: Testicular somatic and germ cells express GM-CSF and GM-CSFR. Our study suggests that testicular GM-CSF is involved in the development of spermatogenesis, which is potentiated by testosterone.

The regenerative ability of the liver is essential for maintaining physiological functions and the injury repair process. The biological mechanisms that regulate liver regeneration remain poorly defined. These mechanisms are notable issues in clinical practice that affect the treatment of hepatic loss caused by hepatectomy, hepatic poisoning, or chronic viral infection. Increasing evidence shows that numerous growth factors, cytokines, and metabolic pathways influence the liver regenerative process. Of particular importance are cytokines and growth factors, which affect different stages of liver regeneration. In this review, we summarize the results obtained from studies that focused on the role of growth factors and cytokines in liver regeneration to reflect on the clinical implications and areas for further study.

Background:  Coronavirus infection can induce the production of inflammatory cytokines leading to acute respiratory distress syndrome (ARDS) and death. It is well-established that interferons (IFNs) are essential in regulating the immune response, thus their effects of IFNs on COVID-19 patients should be subject to investigation. This study aimed to investigate the effects of IFN-α alone or in combination with remdesivir in hospitalized COVID-19 patients.

Material and methods:  A multicentre, retrospective study was conducted on COVID-19 patients admitted to three hospitals in Tehran, Iran, from March 20, 2020, to March 18, 2021. The unadjusted and adjusted effects of IFN-α on COVID-19 outcomes were investigated through propensity score matching (PSM) to achieve a 1:1 balanced dataset.

Results: Among 4,782 patients, 3,764 were eligible for the study, including 1,704 patients (45.27%) receiving at least one treatment with IFN-α and 2,060 controls not receiving IFN-α. After PSM, 851 IFN-α patients and 851 controls were recruited in the PSM analysis with a median age of 60.8 (standard deviation [SD]: 16.2 and 60.9 [SD: 17.4]), respectively. The PSM results showed no significant difference between the survival curves of the IFN-α group and the control group (p=0.340). However, the unadjusted impact of IFN-α on the risk of mortality was statistically significant (p=0.043, hazard-ratio: 0.86; 95% confidence interval [CI]: 0.75-0.99). Also, the combination of IFN-α and remdesivir had no significant benefit (HR: 89, 95% CI: 0.74-1.34).

Conclusion: Our findings indicate that subcutaneous administration of IFN-α, with or without remdesivir, does not have any significant impact on COVID-19 mortality and ICU admission. Future clinical trials considering the time, subtype, and form of IFN-α administration are warranted to investigate the potential therapeutic effects of IFN-α on COVID-19.

Thymic stromal lymphopoietin (TSLP) is highly expressed in the central nervous system in response to inflammation, but its exact function remains unclear. In this study, we used a model of LPS-stimulated microglia to investigate the direct impact of TSLP on microglial activation and the underlying mechanism. We measured oxidative stress, expression of microglial activation markers, and inflammatory indexes. The results show that TSLP treatment increased the expression of TSLP receptors and reduced LPS-induced oxidative stress, inflammation, and the expression of M1-type markers in microglia. Interestingly, TSLP treatment also influenced the differentiation of microglia towards the M2 type, suppressing LPS-induced activation, mediated by the JAK2/STAT5 pathway. Moreover, TSLP also promoted the expression of macrophage markers in the absence of LPS. These findings support the hypothesis that TSLP plays a role in reducing neuroinflammation by blocking the JAK2/STAT5 pathway induced by LPS, thus indicating a regulatory role in the central nervous system. Targeting this cytokine might provide a novel strategy for controlling an inflammatory response in the central nervous system.

Relatively little is known about the relationship between Th1/Th2 cytokines and calculus cholecystitis (CC). The purpose of this study was to investigate the correlation between serum Th1 and Th2 cytokine expression and CC, including both acute and chronic cases. In total, 102 patients with chronic calculous cholecystitis (CCC), 64 patients with acute calculous cholecystitis (ACC), and 55 healthy controls (HCs) were recruited for the study. Serum concentration of Th1 (IL-2, TNF-α, IFN-γ) and Th2 cytokines (IL-4, IL-6, IL-10) was measured at admission and on the fifth day after cholecystectomy using flow cytometry. In addition, the ratio of IL-6/IL-10 was calculated. Correlation of the corresponding factors was then analysed, and univariate and multivariate Cox regression analyses were performed to identify independent markers of ACC severity. Compared to HCs, CCC patients exhibited significantly elevated expression levels of IL-6 and IL-10, while ACC patients demonstrated higher expression of IL-2, TNF-α, and IL-6/ IL-10 in addition to IL-6, and IL-10. In ACC patients, there was a strong positive correlation between IL-6 and IL-10 concentration, the expression of IL-2 was observed to positively correlate with serum ALT and AST concentration, and TNF-α expression positively correlated with the duration of hospitalization. Moreover, patients with moderate-to-severe ACC presented with higher expression of IL-10 compared to those with mild ACC. Cox regression analysis confirmed that IL-10 and IL-6 were independent factors for the severity of ACC. Following surgery, the levels of IL-6 and IL-6/IL-10 significantly decreased but did not fully return to baseline levels in ACC patients. Our study reveals atypical Th1/Th2 cytokine expression profiles in patients with acute and chronic CC, and further highlights the significant potential of these cytokines, particularly IL-6 and IL-10, in assessing the severity and progression of CC.

Polyclonal antisera from patients have been at the basis of the description of autoimmune diseases and today monoclonal antibodies are widely used in the therapy of cancer and many inflammatory diseases. How antisera and antibodies in combination with traditional in vitro and in vivo biological test systems have been instrumental reagents for the discovery of new cytokines is illustrated here for interleukin-1, -6 and -8. Furthermore, widely used immunological detection/quantification systems, such as ELISAs and multiplex assays, based on the use of either polyclonal or monoclonal antibodies, are often fraught with misinterpretations, because the results are affected by the possible occurrence of posttranslational modifications (PTMs) of the analytes. Cytokines and chemokines are present in vivo as mixtures of proteoforms with different amino- or carboxytermini or carrying heterogeneous glycan chains and possibly also being subject to citrullination, pyroglutamination and other PTMs. Increased knowledge about the specificities of antibody (cross)reactivities with cytokine ligands have improved diagnosis and treatment of many diseases, with inflammatory processes, including cancer-associated inflammation, at the frontline.

Background and objective: Endothelial cell activation plays a critical role in leukocyte recruitment during inflammation and infection. We previously found that cholinergic stimulation (via vagus nerve stimulation) attenuates vascular endothelial impairment and reduces the inflammatory profile in ovariectomized rats. However, the specific molecular mechanism is unclear. This study was designed to explore the effects and molecular mechanisms of cholinergic agonists (acetylcholine [ACh]) on lipopolysaccharide (LPS)-induced endothelial cell activation in vitro.

Methods: Human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of LPS (10/100/1000 ng/mL) to activate endothelial cells. HUVECs were untreated, treated with ACh (10-5 M) alone, treated with 100 ng/mL LPS alone, or treated with different concentrations of ACh (10-9/10-8/10-7/10-6/10-5 M) before LPS stimulation. HUVECs were also pre-treated with 10-6 M ACh with or without mecamylamine (an nAChR blocker) (10 μΜ) and methyllycaconitine (a specific α7 nAChR blocker) (10 μΜ) and incubated with or without LPS. ELISA, western blotting, cell immunofluorescence, and cell adhesion assays were used to examine inflammatory cytokine production, adhesion molecule expression, monocyte-endothelial cell adhesion and activation of the MAPK/NF-κB pathways.

Results: LPS (at 10 ng/mL, 100 ng/mL and 1,000 ng/mL) increased VCAM-1 expression in HUVECs in a dose-dependent manner (with no significant difference between LPS at 100 ng/mL and 1,000 ng/mL). ACh (10-9 M-10-5 M) blocked adhesion molecule expression (VCAM-1, ICAM-1, and E-selectin) and inflammatory cytokine production (TNF-α, IL-6, MCP-1, IL-8) in response to LPS in a dose-dependent manner (with no significant difference between 10-5 and 10-6 M Ach). LPS was also shown to significantly enhance monocyte-endothelial cell adhesion, which was largely abrogated by treatment with ACh (10-6M). VCAM-1 expression was blocked by mecamylamine rather than methyllycaconitine. Lastly, ACh (10-6 M) significantly reduced LPS-induced phosphorylation of NF-κB/p65, IκBα, ERK, JNK and p38 MAPK in HUVECs, which was blocked by mecamylamine.

Conclusions: ACh protects against LPS-induced endothelial cell activation by inhibiting the MAPK and NF-κB pathways, which are mediated by nAChR, rather than α7 nAChR. Our results may provide novel insight into the anti-inflammatory effects and mechanisms of ACh.

Although mesenchymal stem cells (MSCs) have exhibited promising immunomodulatory potential in preclinical studies, clinical studies have revealed variable results. These results often depend on environmental cues. Pre-conditioning MSCs with cytokines is one of the methods used to enhance their immunomodulatory effects. In this study, we harvested adipose-derived MSCs from mice and cultured them with different doses of the cytokine, IFN-γ, and the corticosteroid drug, dexamethasone, in order to investigate their effects on MSC immunosuppressive function. We found the co-culture or supernatant of MSCs, pre-conditioned with IFN-γ, together with spleen mononuclear cells resulted in a significant reduction of mononuclear cell proliferation. Although the supernatant of MSCs, pre-conditioned with dexamethasone, showed similar results, dexamethasone pre-conditioning of co-cultured MSCs increased mononuclear cell proliferation. The results further our understanding of immune-related effects of MSCs which may provide a basis for further in vivo studies to achieve better clinical results. We propose that pre-conditioning with cytokines might be an effective method to boost the immunomodulatory effects of MSCs.