OBJECTIVES:B-cell lymphoma exhibits significant clinical heterogeneity, necessitating improved biomarkers for risk stratification. C-C chemokine receptor 7 (CCR7) and trimethylation of histone H3 lysine 9 (H3K9me3) are implicated in cellular senescence and tumor invasion. While the clinical significance of their co-expression in lymphomagenesis remains unclear. This study aims to define the expression profiles of CCR7 and H3K9me3 in B-cell lymphoma, explore their correlation with aggressive clinical indicators, and evaluate their combined prognostic value. METHODS:The expression of CCR7 and H3K9me3 in tumor tissues from B-cell lymphoma patients was analyzed by immunohistochemical (IHC) double-staining. The mechanistic association between the two was verified by co-immunoprecipitation assays and Western blot (WB) experiments detecting changes in cellular H3K9me3 levels following CCR7 ligand stimulation. The association between co-expression and patient clinical parameters, tumor burden, and progression-free survival (PFS) was evaluated through correlation analysis, Kaplan-Meier survival curves, and Cox regression analysis. RESULTS:H3K9me3 expression was predominantly nuclear, whereas CCR7 was expressed on the cell membrane. Both markers were significantly upregulated in aggressive lymphomas and positively correlated with LDH, β2-microglobulin, and neutrophil percentage. An interaction between CCR7 and H3K9me3 could be demonstrated in that CCR7 ligand stimulation resulted in an upregulation of H3K9me3 expression. Enhanced H3K9me3 expression was associated with bone marrow infiltration. High expression of CCR7 was associated with poorer progression-free survival (PFS), whereas high expression of both CCR7 and H3K9me3 identified patients with the worst prognosis. Univariate and multivariate Cox regression analysis indicated that the combined expression was a potential prognostic biomarker for B-cell lymphoma. CONCLUSION:Co-elevated CCR7 and H3K9me3 expression defines a high-risk B-cell lymphoma subgroup with high tumor burden, bone marrow infiltration, and poor prognosis, highlighting their potential as biomarkers for risk stratification and candidate therapeutic targeting.
Psoriasis is a challenging immune-mediated dermatological disorder with an urgent need for effective clinical therapeutics, while astilbin has shown considerable efficacy in suppressing psoriasis progression, its underlying mechanisms are not fully clarified. This study aimed to systematically investigate the anti-psoriatic effects of astilbin and to elucidate its potential mechanisms of action. A psoriasis-like mouse model was established via cold water swimming, dietary restriction, and topical application of 5% propranolol emulsion, followed by daily treatment with low- (25.6 mg/kg), middle- (51.2 mg/kg), or high-dose (76.8 mg/kg) astilbin for 6 consecutive days, with evaluations including PASI scoring, histopathological examination, Baker scoring, inflammatory cytokine detection, and flow cytometric analysis of lymphocyte populations in lymph nodes and spleen. Middle and high doses of astilbin significantly reduced skin lesions and erythema, with PASI scores decreasing by 23.6%, and 44.9% respectively, Baker scores significantly reduced by 23.1% and 24.1% in the middle- and high-dose groups, and astilbin also significantly suppressed skin IL-17A, IL-6, and IFN-γ levels; moreover, middle and high doses substantially downregulated Th1, Th17, and Treg cell populations in lymph nodes and effectively restored Th17/Treg balance. Astilbin effectively ameliorates psoriatic skin lesions through immunomodulatory mechanisms involving the correction of lymph node Th17/Treg imbalance, highlighting its potential as a therapeutic agent for psoriasis.
Interferon-stimulated gene 15 (ISG15) is a small ubiquitin-like protein that can be conjugated to its target proteins through an enzymatic cascade known as ISGylation, thereby altering their function. Elevated levels of free ISG15 (non-conjugated) and ISGylation are observed in several cancer types, including medulloblastoma (MB) a malignant pediatric cerebellar tumor categorized into four molecular subgroups: Wingless, Sonic Hedgehog, Subgroup 3 (G3), and Subgroup 4 (G4). However, ISG15 gene expression in MB remains unexplored. In this study, we evaluated the ISG15 protein levels, the expression of the ISG15 and ISGylation system, and interferon gamma signaling mediators in human MB samples to propose the role of ISG15 in this tumoral context. ISG15 expression in MB samples was comparatively analyzed against normal tissue using the Oncopression database. Expression levels were further assessed in various pediatric tumors within the Childhood Brain Tumor Tissue Consortium dataset via the University of Alabama at Birmingham Cancer Data Analysis Portal database. ISG15 protein abundance in MB samples was then evaluated via immunohistochemistry on a tumor tissue microarray. To broaden the analysis, ISG15 expression was profiled across multiple MB cell lines using the R2 Genomics Analysis and Visualization Platform. Finally, to determine clinical significance, the association between ISG15 expression and patient survival was assessed using Kaplan-Meier analysis. ISG15 expression was significantly lower in MB samples than in other pediatric tumors (p < 0.05) and normal tissue (p < 0.0001). Immunohistochemical analysis further confirmed a marked reduction in ISG15 protein abundance in MB samples compared to healthy tissue (p < 0.001). Elevated ISG15 levels correlated with improved survival outcomes in the G3 and G4 subgroups (p < 0.05). ISG15 is downregulated in MB tissues compared to controls. High ISG15 expression within the G3/G4 MB subgroups correlates with prolonged survival, suggesting a potential tumor-suppressive function. These results collectively indicate that ISG15 may serve as a valuable prognostic biomarker for G3/G4 MB patients.
The expression of the interleukin-6 (IL-6) gene promoter and its variations in postmenopausal women of Javanese ethnicity remains unexplored. This study aimed to examine IL-6 promoter polymorphisms at positions -174G/C, -572G/C, -597A/G, and -634C/G and their associations to osteoporosis status in Javanese postmenopausal women. A cross-sectional study was conducted at an elderly integrated service post in Sidoarjo, Indonesia. Among 699 screened individuals, 66 postmenopausal women fulfilled the inclusion and exclusion criteria. Bone mineral density was assessed using dual-energy X-ray absorptiometry (DXA), and osteoporosis status was defined based on T-score values. IL-6 promoter polymorphisms were genotyped by sequencing PCR-amplified promoter regions. IL-6 mRNA expression was assessed using RT-PCR followed by densitometric analysis, and serum IL-6 concentrations were determined using enzyme-linked immunosorbent assay. Our study showed that osteoporosis and osteopenia were predominant (28.8% and 57.6%, respectively), and 13.6% of subjects had normal BMD. The IL-6 promoter variant genotypes and frequencies were as follows: at -174 GG (0.924), CC (0.045), and GC (0.030); at -572 GC (0.424), CC (0.406), and GG (0.167); at -597 GG (0.924) and GA (0.0758) GA (0.076); and at -634 CC (1). The IL-6 mRNA and protein level (median 6.06, IQR 5.0398 pg/mL) were not statistically different among individuals with different genotypes and with normal, osteopenia, or osteoporosis status. Ordinal regression showed that IL-6 promoter polymorphisms were not significantly associated with osteoporosis status. The polymorphisms of the IL-6 promoter were detected in Javanese postmenopausal women; however, such polymorphisms did not correlate with IL-6 mRNA and protein levels nor osteoporosis status. IL-6 promoter polymorphisms were present in Javanese postmenopausal women; however, these variants were not associated with IL-6 expression at the mRNA or protein level, nor with osteoporosis status.
Glioblastoma is a lethal primary brain tumor that is therapeutically challenging due to its rapid progression. Interferon-gamma (IFN-γ) signaling is altered in glioblastoma. Moreover, proteolytic enzymes, known as proteases, have been linked to the invasive growth of cancerous cells. In this study, we aimed to identify a glioblastoma-associated protease group and to determine its potential connection with IFN-γ signaling. Using cancer expression databases, we analyzed the differential expression of 35 proteases in glioblastoma and healthy brain tissue, and the relevance of their deregulation to patient survival. We also explored correlations between IFN-γ signaling element expression and upregulated proteases in glioblastoma. Additionally, we analyzed the effect of IFN-γ on the levels of these 35 proteases using a protein microarray and found that cathepsin L (CTSL) was upregulated by IFN-γ. Then, we analyzed the modulation of CTSL by IFN-γ in glioblastoma cells using dot blot, western blot, and immunofluorescence assays. We identified 11 proteases (cathepsin B, Z, C, S (CTSB, CTSZ, CTSC, CTSS), matrix metalloproteinase 2, 7, 9 (MMP2, MMP7, MMP9), a disintegrin and metalloproteinase 9 (ADAM9), urokinase-type plasminogen activator (PLAU), presenilin 1 (PSEN1), and CTSL that were upregulated in glioblastoma tissue compared to healthy brain tissue. The expression of specific elements of the IFN-γ pathway correlated with the expression of some of these proteases in glioblastoma samples. Moreover, IFN-γ affected the intracellular and extracellular levels of proteases (four were upregulated and six were downregulated) in glioblastoma-derived cells. Hence, IFN-γ signaling may play a role in glioblastoma by regulating the expression of some proteases. The CTSL protease was upregulated by IFN-γ and was associated with poor glioblastoma prognoses. Thus, we revealed a protease profile (ADAM9, CTSB, MMP7, CTSC, CTSL, MMP9, and PLAU) associated with glioblastoma progression and further demonstrated that CTSL is regulated by IFN-γ in glioblastoma cells. These results establish a link between IFN-γ signaling and protease regulation in glioblastoma.
Immunotherapy has demonstrated limited efficacy in immunologically "cold" breast cancers characterized by absent T-cell infiltration and inadequate interferon signaling. The purpose of this work is to propose and articulate a mechanistic and therapeutic framework in which mitochondrial stress is deliberately harnessed to convert immunologically "cold" breast tumors into "hot," T cell-inflamed, immunotherapy-responsive lesions. This review synthesizes emerging evidence positioning mitochondrial stress as a strategic lever to transform these immune-excluded tumors into inflamed, therapy-responsive lesions. We examine how mitochondrial dysfunction triggers cytosolic release of mitochondrial DNA (mtDNA), a potent damage-associated molecular pattern that activates the cGAS-STING pathway, initiating type I interferon responses and secretion of T-cell-recruiting chemokines such as CCL5 and CXCL10. This axis functions as a "double-edged sword"-while acute activation converts "cold" tumors into "hot" immune-responsive states, chronic engagement drives immunosuppressive cytokine networks and therapeutic resistance, with outcomes varying across breast cancer subtypes. We explore six combination therapeutic strategies: mitochondrial poisons, radiotherapy/chemotherapy, PARP/ATR inhibitors, metabolic reprogramming agents, mitochondrial quality control modulators, and localized mitochondrial stress induction, each paired with immune checkpoint blockade. The review emphasizes "controlled ignition" as a paradigm whereby precisely dosed mitochondrial stress amplifies tumor antigenicity and favorable cytokine landscapes while avoiding chronic immunosuppression. Cytokine networks emerge as both integrators and therapeutic targets of mitochondrial-immune crosstalk. Future advances require mapping subtype-specific thresholds, developing tumor-restricted delivery systems, and implementing biomarker-guided trials to safely harness mitochondrial stress, potentially redefining these organelles as programmable immunological adjuvants in breast cancer therapy.
Type I interferons, which play an important role in the pathogenesis of various autoimmune diseases such as systemic lupus erythematosus (SLE), are expressed at very low levels under physiological conditions. In this study, we focused on IFN-beta (IFN) β-for its potential use as a biomarker of SLE activity and compared three different technologies for its quantification in the serum of healthy donors and patients with SLE. A total of 93 serum samples from healthy donors and 463 serum samples from lupus patients were tested using either ELISA, digital ELISA based on Single Molecule Array (Simoa®) technology, or a novel ultrasensitive immunoassay (S-Plex®) based on electrochemiluminescence. Circulating IFNβ- levels were detected in 1.3%, 6.7%, and 100% of healthy donors by Simoa, ELISA, and S-Plex technology, respectively. In patients with SLE, circulating IFNβ- levels were detected in 7.5%, 18.8%, and 98.3% by Simoa, ELISA, and S-Plex technology, respectively, demonstrating the utility of the S-Plex technology for quantifying this cytokine in serum. S-Plex-determined serum IFNβ- concentrations were higher in patients with SLE than in healthy donors (median, 0.297 pg/mL vs 0.205 pg/mL, p=0.0004, respectively), in patients with active SLE compared to those with inactive SLE (0.389 pg/mL vs 0.243 pg/mL, p=0.0013, respectively), in patients with severe flare compared to those without flare (0.462 pg/mL vs 0.244 pg/mL, p=0.0009, respectively), and in patients not in remission compared to those in remission (0.374 pg/mL vs 0.239 pg/mL, p=0.0027, respectively). However, according to ROC curve analyses, S-Plex- determined serum IFNβ- levels demonstrated poor diagnostic performances for distinguishing disease clinical status in SLE. Using S-Plex technology, circulating IFNβ- levels are quantifiable in the serum of healthy donors and are significantly higher in patients with SLE. They increase significantly in patients with clinically active disease. Although IFNβ- is a biomarker of SLE activity, its serum levels in patient groups show considerable overlap, making it difficult to reliably distinguish between different states of disease activity.
Interleukin-33 (IL-33), a key member of the IL-1 family, plays a significant role in inflammation and cancer. Its classic receptors, ST2 and IL-1 receptor accessory protein (IL-1RAcP), are predominantly expressed in immune cells such as T helper 2 (Th2) cells and mast cells. Recent studies have highlighted the involvement of IL-33 in breast cancer, demonstrating its ability to exert dual functional effects by modulating both innate and adaptive immune responses within the tumour microenvironment. However, the precise molecular mechanisms linking IL-33 to breast cancer pathogenesis and its potential as a target for molecularly targeted therapies remain incompletely understood. This review aims to provide a comprehensive summary of the current understanding of IL-33 in breast cancer immunotherapy.
Since their discovery, chemotactic cytokines or chemokines have been intensively studied for about half a century. Chemokines originate from tissue cells, leukocytes, blood platelets and plasma. Here, we review a number of seminal findings on plasma chemokines within an historical and international context. These aspects include how induction and purification protocols led to the discovery of a new family of mediators, named chemokines, on the basis of protein sequencing; how molecular cloning techniques facilitated discoveries of additional family members on the basis of conserved protein structures; how blood plasma and platelets were used as a source of inducible and constitutively expressed chemokines; how various forms of proteolytic reactions may convert precursor proteins into chemokines and either potentiate or inactivate their activity; how abundancy classes and synergism should be interpreted through critically considering plasma chemokine biology; and how other blood proteins, such as serum amyloid A, interact in functional terms with CXC and CC chemokines. The gradual dissection of all these elements not only reveals the complexity of chemokine actions, but also stimulates a more comprehensive interpretation of chemokine levels in plasma and serum, with future chemokinome analyses in mind.
Interleukin-6 (IL-6) is a cytokine with pleiotropic effects that plays a significant role in the transition from the innate immune response to adaptive response. IL-6 is of interest due to its proinflammatory action, however, it also exhibits anti-inflammatory effects, supporting metabolism and suppressing associated diseases, such as obesity, diabetes mellitus and metabolic syndrome. The IL-6 receptor (IL-6R) is a type I transmembrane glycoprotein in the plasma membrane of only some cell types, such as macrophages, neutrophils, hepatocytes, and T cells. The function of IL-6R requires another transmembrane glycoprotein of 130 kDa (gp130) which, in contrast to IL-6R, is expressed in many cell types. In addition, a soluble form of the IL-6 receptor (sIL-6R) also plays a role in the function of IL-6. These receptors, gp130 and sIL-6R, are involved in the trans pathway of IL-6 signalling, the activation of which is associated with high IL-6 concentrations, promoting proinflammatory processes that are well known. In contrast, the physiological effects of IL-6 associated with increased insulin secretion, fatty acid oxidation and decreased adipose tissue, which occur due to activation of the IL-6 anti-inflammatory signalling pathway, have been poorly explored. Some studies using IL-6 knockout models suggest that some of the anti-inflammatory effects of IL-6 may be stimulated by low concentrations of IL-6, and are essential to suppressing metabolic alterations. This review seeks to highlight the importance of the anti-inflammatory role of IL-6 in metabolic diseases.
The blood-brain barrier (BBB) consists of a unique system of brain microvascular endothelial cells, capillary basement membranes, and terminal branches ("end-feet") of astrocytes. The BBB's primary function is to protect the central nervous system from potentially harmful or toxic substances in the bloodstream by selectively controlling the entry of cells and molecules, including nutrients and immune system components. During neuroinflammation, the BBB loses its integrity, resulting in increased permeability, mostly due to the activity of inflammatory cytokines. However, the pathomechanism of structural and functional changes in the BBB caused by individual cytokines is poorly understood. This review summarizes the current state of knowledge on this topic, which is important from both the pathophysiological and clinical-therapeutic point of view. The structure and function of each of the components of the BBB are discussed with particular attention to phenotypic differences between brain microvascular endothelial cells and the vascular endothelium at other locations of the circulatory system. The protein composition of the inter-endothelial tight junctions in the context of regulating BBB permeability is presented, as is the role of the pericyte-BMEC interaction in the exchange of metabolites, ions, and nucleic acids. Finally, the documented actions of proinflammatory cytokines within the BBB are summarized.
Pancreatic cancer (PC) is one of the leading causes of cancer deaths, associated with a high risk of metastasis and mortality. The long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is highly expressed in multiple types of tumour tissues and may be associated with the growth of PC cells. In this study, we aimed to assess the role and possible mechanisms of MALAT1 in PC progression. Methods: Expression of MALAT1 was studied by quantitative real-time polymerase chain reaction (qRT-PCR) in PC tissues. The dual-luciferase assay was performed to validate binding between MALAT1 and miR-141-5p in HEK293 cells. Western blot analysis was performed to examine the expression of transforming growth factor beta (TGF-(3) and its receptors, TGFBR1 and TGFBR2. Invasiveness and migration of cultured PANC-1 cells were studied using transwell invasion and migration assays, respectively. Results: A high level of miR-141-5p and low level of MALAT1 were detected in PC tissues, and the level of MALAT1 was shown to significantly correlate with tumour growth and metastasis. In HEK293 cells, miR-141-5p overexpression inhibited the expression of TGFBR1 and TGFBR2, and this inhibition was reversed by overexpression of MALAT1. In PANC-1 cells, MALAT1 was shown to act as a competing endogenous RNA, as the direct target of miR-141-5p. Furthermore, in PANC-1 cells, miR-141-5p overexpression suppressed TGF-induced epithelial-mesenchymal transition (EMT), cell migration, and cell invasion through direct binding to the 3'UTR of TGFBR1 and TGFBR2. Conclusions: Our results indicate that, in PC cells, miR-141-5p suppresses TGFBR1 and TGFBR2 expression and further inhibits TGF-(3-induced EMT, cell migration, and cell invasion, which are reversed by overexpression of MALAT1, demonstrating that MALAT1 and miR-141-5p may be important regulators in the initiation and metastasis of PC.
The aim of the present study was to evaluate the diagnostic significance of the dynamics of cytokines and growth factors during pregnancy with and without preeclampsia. The study included 168 pregnant women at risk of hypertensive disorders. The levels of biomarkers of all pregnant women were studied at 12-16 weeks, 28-30 weeks and 36-38 weeks. These included cytokines (tumour necrosis factor-α, interferon-, γinterleukin-4) and growth factors (placental growth factor, vascular endothelial growth factor). All pregnant women were divided into two groups: 124 patients with preeclampsia and 44 without preeclampsia (control group). In patients with preeclampsia, an increase in the level of tumour necrosis factorα- was observed, compared with the control group: a 6.1-fold increase at 12-16 weeks and a 5.9-fold increase at 36-38 weeks. The level of interferon-γ was also increased, by 44.3% in the first trimester of pregnancy and by 46.8% at 28-30 weeks, compared to the control group. The level of interleukin-4 did not significantly differ between the studied groups. The level of placental growth factor was reduced in pregnant women with preeclampsia at all stages of gestation, and at 28-30 weeks was reduced by 67.9% compared to the control group. The level of vascular endothelial growth factor was also reduced, by 75%, compared with the control group. An increase in the level of pro-inflammatory cytokines and decrease in growth factors may therefore be considered as potential predictors of the development of preeclampsia, and evaluation of these factors may be advocated in pregnant women with risk factors of preeclampsia.
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. 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. Among 4,782 patients, 3,764 were eligible for the study, including 1,704 patients (45.27
COVID-19 vaccination and acute infection result in cellular and humoral immune responses with various degrees of protection. While most studies have addressed the difference in humoral response between vaccination and acute infection, studies on the cellular response are scarce. We aimed to evaluate differences in immune response among vaccinated patients versus those who had recovered from COVID-19. Materials and Methods: This was a prospective study in a tertiary medical centre. The vaccinated group included health care workers, who had received a second dose of the BNT162b2 vaccine 30 days ago. The recovered group included adults who had recovered from severe COVID-19 infection (<94% saturation in room air) after 3-6 weeks. Serum anti-spike IgG and cytokine levels were taken at entry to the study. Multivariate linear regression models were applied to assess differences in cytokines, controlling for age, sex, BMI, and smoking status. Results: In total, 39 participants were included in each group. The mean age was 53 +/- 14 years, and 53% of participants were males. Baseline characteristics were similar between the groups. Based on multivariate analysis, serum levels of IL-6 (beta=-0.4, p<0.01), TNF alpha (beta=-0.3, p=0.03), IL-8 (beta=-0.3, p=0.01), VCAM-1 (beta=-0.2, p<0.144), and MMP-7 (beta=-0.6, p<0.01) were lower in the vaccinated group compared to the recovered group. Conversely, serum anti-spike IgG levels were lower among the recovered group (124 vs. 208 pg/mL, p<0.001). No correlation was identified between antibody level and any of the cytokines mentioned above. Conclusions: Recovered COVID-19 patients had higher cytokine levels but lower antibody levels compared to vaccinated participants. Given the differences, these cytokines might be of value for future research in this field.
Primary Sjögren syndrome (pSS) is a systemic autoimmune disorder that affects various systems in the body, resulting in symptoms such as dry eyes and mouth, pain, and fatigue. Inflammation plays a critical role in pSS and its associated complications, with chronic inflammation being a common occurrence in patients with pSS. This review of the literature highlights inflammatory markers that could serve as indicators to predict disease progression in pSS. Laboratory markers are frequently and significantly increased in pSS patients, including erythrocyte sedimentation rate, C-reactive protein, complement proteins, S100 proteins, cytokines (IFNs, CD40 ligand, soluble CD25, rheumatoid factors, interleukins, and TNF-α), and chemokines (CXCL13, CXCL10, CCL2, CXCL11, and CCL25). These inflammatory markers can be used as prognostic indicators for disease progression in pSS. In conclusion, the results from the studies reported in this review indicate that high levels of inflammatory markers may serve as markers for disease progression of pSS, which, in turn, may be valuable in predicting disease outcome.
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.
