Cytokine Network Research Articles

Synthesis of cytokines during physiological pregnancy

The article is devoted to the study of the level of pro- and anti-inflammatory cytokines in women with a physiological pregnancy, which is of great importance in obstetrics. Studying the synthesis of cytokines makes it possible to identify disturbances in the course of pregnancy, which is of great practical importance. The authors conducted a study of the level of cytokines in women with physiological pregnancy. Purpose of the study: to study the serum concentration of pro-inflammatory (IL-1β, IL-6, TNFα, IFNγ) and anti-inflammatory (IL-4, IL-10) cytokines in the dynamics of physiological pregnancy. The level of serum cytokines was studied in 94 women with a physiologically progressing pregnancy, who were registered with advisory clinics No. 14, No. 26, and No. 28 in Bukhara. The age of pregnant women ranged from 21 to 37 years, averaging 26.3±1.5 years. When compiling groups by trimester of pregnancy, it was revealed that: 35 women were in the first trimester of pregnancy; in 31 – the second trimester; and in 28 women – the third trimester of pregnancy. The control group consisted of 30 practically healthy non-pregnant women who were comparable in age. The levels of cytokines 1β, IL-6, TNFα, IFNγ, IL-4, and IL-10 was determined in peripheral blood serum using a set of reagents produced by Cytokin LLC (St. Petersburg, Russia) using the ELISA method according to the manufacturer’s instructions. Statistical processing of the obtained results was carried out using Student’s t-test using the standard Windows 2000 statistical software package. An increase in the level of proinflammatory cytokines (IFNγ, TNFα) was detected in the early stages of gestation compared with data from healthy non-pregnant women, which persisted in the second half of pregnancy against the background of an increase in anti-inflammatory cytokines (IL-4, IL-10). In the third trimester of pregnancy, a further increase in the serum level of pro-inflammatory cytokines (IL-1β, TNFα, IFNγ) was observed. The results of the studies indicate that at the level of the cytokine network there are mechanisms of fetoprotection, the violation of which can be the cause of pregnancy pathology.

Circulating CD31 and resistin levels reflect different stages of coronary atherosclerosis in patients with psoriasis.

Psoriasis is a skin disease with a complicated pathophysiology that includes an extensive inflammatory cytokine network. Nevertheless, the relationship between psoriasis severity, cytokine levels, and coronary artery atherosclerosis remains poorly understood. Our aim was to find serum markers as potential candidates for cardiovascular disease (CVD) risk monitoring in patients with psoriasis. Therefore, we examined coronary artery atherosclerosis via coronary computed tomography angiography (CCTA), serum cytokine levels via multiple immunoassays, and the patients' psoriasis state. Our findings reveal for the first time that the mainstream psoriasis cytokines interleukin 17A (IL-17A), IL-19, and IL-36 in the sera of Japanese patients with psoriasis showed a linear regression association with the Psoriasis Area and Severity Index score. Furthermore, the serum level of IL-19 was remarkably correlated to Th2-related serum cytokines such as IL-4 and IL-17E. When we investigated potential markers to monitor CVD in patients with psoriasis, circulating cluster of differentiation 31 (CD31) and resistin, but not psoriasis-related cytokines, were expressed differently at each stage of coronary atherosclerosis by CCTA. CD31 and resistin levels rose dramatically in individuals with psoriasis vulgaris (PV) and noncalcified atherosclerosis. In contrast, CD31 was negatively correlated with the coronary artery calcification score (CACS) in patients with PV, whereas resistin was inversely correlated with CACS in patients with psoriatic arthritis. In conclusion, the axis of IL-17A, IL-19, and IL-36 remains associated with the severity of psoriasis during the chronic phase of the disease, regardless of the application of topical or systemic treatment. Monitoring the levels of these cytokines can accurately determine the severity of skin inflammation. Resistin and CD31 are linked to coronary artery lesions and might be good candidates for tracking the progression of coronary atherosclerosis in patients with psoriasis.

Immunoregulatory role of AC007278.3 and HOTAIR long non-coding RNAs in lupus nephritis: potential biomarkers and therapeutic targets.

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in various biological processes, including immune regulation and autoimmune pathologies. However, their specific significance in modulating the cytokine network in systemic lupus erythematosus (SLE) remains largely unexplored. This study assessed the expression patterns of immune-related lncRNAs, HOTAIR, and AC007278.3, along with their related protein-coding genes, TNF-α and IL18RAP, in nephritic SLE patients. Additionally, the potential of selected genes as diagnostic biomarkers for SLE was evaluated. Blood samples were obtained from SLE patients (n = 30) and age-sex-matched healthy controls (HCs) (n = 60). Subsequently, RNA was isolated from peripheral blood mononuclear cells (PBMCs), and cDNA was synthesized to analyze the expression levels of the target genes using real-time PCR. The correlation analysis between the relative expressions of different genes was examined in both the patient and HC groups. The diagnostic potential of the lncRNAs was determined by calculating the Area Under the Curve of the Receiver Operating Characteristics (AUC of ROC), Cut-off, sensitivity, and specificity. Our results indicated a significant upregulation of lncRNAs AC007278.3 (fold change [FC] = 14.13, p-value < 0.0001) and HOTAIR (FC = 14.1, p-value < 0.0001). Correspondingly, their associated target genes, TNF-α and IL18RAP, were also overexpressed in patients (FC = 2.66 and FC = 5.18, respectively, p-value < 0.001). Notably, a strong positive correlation was observed between IL18RAP and AC007278.3 in SLE patients. Moreover, the AUC of ROC analyses underscored the diagnostic efficacy of AC007278.3 alone and combined with HOTAIR, yielding values of 0.89 and 0.86, respectively. These findings highlight the potential immunoregulatory roles of lncRNAs AC007278.3 and HOTAIR, emphasizing their significance as promising diagnostic biomarkers and potential therapeutic targets for SLE. Additionally, they provide valuable insights into the molecular mechanisms underpinning the disease's pathogenesis.

Spatial multiomics reveal intratumoral immune heterogeneity with distinct cytokine networks in lung cancer brain metastases.

The tumor microenvironment of brain metastases has become a focus in the development of immunotherapeutic drugs. However, countless brain metastasis patients have not experienced clinical benefit. Thus, understanding the immune cell composition within brain metastases, and how the immune cells interact with each other and other microenvironmental cell types, may be critical for optimizing immunotherapy. We applied spatial whole transcriptomic profiling with extensive multiregional sampling (19-30 regions per sample) and multiplex immunohistochemistry on formalin-fixed, paraffin-embedded lung cancer brain metastasis samples. We performed deconvolution of gene expression data to infer the abundances of immune cell populations and inferred spatial relationships from the multiplex immunohistochemistry data. We also described cytokine networks between immune and tumor cells and used a protein language model to predict drug-target interactions. Finally, we performed deconvolution of bulk RNA data to assess the prognostic significance of immune-metastatic tumor cellular networks. We show that immune cell infiltration has a negative prognostic role in lung cancer brain metastases. Our in-depth multiomics analyses further reveal recurring intratumoral immune heterogeneity and the segregation of myeloid and lymphoid cells into distinct compartments that may be influenced by distinct cytokine networks. By employing computational modeling, we identify drugs that may target genes expressed in both tumor core and regions bordering immune infiltrates. Finally, we illustrate the potential negative prognostic role of our immune-metastatic tumor cellular networks. Our findings advocate for a paradigm shift from focusing on individual genes or cell types, towards targeting networks of immune and tumor cells.

Proteomics Reveals Divergent Cardiac Inflammatory and Metabolic Responses After Inhalation of Ambient Particulate Matter With or Without Ozone.

Inhalation of ambient particulate matter (PM) and ozone (O3) has been associated with increased cardiovascular morbidity and mortality. However, the interactive effects of PM and O3 on cardiac dysfunction and disease have not been thoroughly examined, especially at a proteomic level. The purpose of this study was to identify and compare proteome changes in spontaneously hypertensive (SH) rats co-exposed to concentrated ambient particulates (CAPs) and O3, with a focus on investigating inflammatory and metabolic pathways, which are the two major ones implicated in the pathophysiology of cardiac dysfunction. For this, we measured and compared changes in expression status of 9 critical pro- and anti-inflammatory cytokines using multiplexed ELISA and 450 metabolic proteins involved in ATP production, oxidative phosphorylation, cytoskeletal organization, and stress response using two-dimensional electrophoresis (2-DE) and mass spectrometry (MS) in cardiac tissue of SH rats exposed to CAPs alone, O3 alone, and CAPs + O3. Proteomic expression profiling revealed that CAPs alone, O3 alone, and CAPs + O3 differentially altered protein expression patterns, and utilized divergent mechanisms to affect inflammatory and metabolic pathways and responses. Ingenuity Pathway Analysis (IPA) of the proteomic data demonstrated that the metabolic protein network centered by gap junction alpha-1 protein (GJA 1) was interconnected with the inflammatory cytokine network centered by nuclear factor kappa beta (NF-kB) potentially suggesting inflammation-induced alterations in metabolic pathways, or vice versa, collectively contributing to the development of cardiac dysfunction in response to CAPs and O3 exposure. These findings may enhance understanding of the pathophysiology of cardiac dysfunction induced by air pollution and provide testable hypotheses regarding mechanisms of action.

Major depressive disorder, neuroticism, suicidal behaviors, and depression severity are associated with cytokine networks and their intricate interactions with metabolic syndrome

ObjectivesTo identify alterations in the immune profiles in outpatients with major depression (MDD), and its associations with key features, such as suicidal ideation, neuroticism, cognitive symptoms, and the depression phenome while accounting for metabolic syndrome (MetS). MethodsIn this case-control study, we assayed 48 serum cytokines, chemokines, and growth factors in 67 healthy controls and 66 MDD outpatients. Around 50 % of the outpatient MDD and control participants had a diagnosis of MetS. ResultsTen differentially expressed proteins (DEPs) were upregulated in outpatient MDD (i.e., CXCL12, tumor necrosis factor [TNF]β, platelet-derived growth factor [PDGF], CCL11, interleukins [IL]9, IL4, CCL5, CCL2, CCL4, IL1 receptor antagonist [IL1RN]), indicating an immune and defense response. Six DEPs were downregulated (vascular endothelial growth factor A [VEGFA], IL12, CCL3, colony stimulating factor [CSF]1, IL1B, nerve growth factor [NGF]), indicating lowered neurogenesis and neuron death regulation. Significant interactions between outpatient MDD and MetS caused a) substantial increases in IL4, IL17, TNF, TNFB, CCL2, CCL5, PDGF, IL1RN; and b) downregulation of VEGFA and FGF. A large part of the variance in neuroticism (26 %), suicidal behaviors (23 %), and the MDD phenome (31 %) was predicted by immunological data and interactions between MetS and CCL5, TNFB or VEGFA. ConclusionOutpatient MDD is characterized by a cytokine profile with neurotoxic potential which partly explains neuroticism, suicidal behaviors, and the phenome's severity. Lowered IL-10 and activated cytokine profiles with neurotoxic potential are characteristics of outpatient MDD and other depression phenotypes, including severe first-episode inpatient MDD. The presence of MetS in outpatient MDD considerably activates immune profiles with neurotoxic potential. Consequently, immune studies in MDD should always be performed in subjects with and without MetS.

The role of selected cytokines from the interleukin-1 family in the peritoneal fluid of women with endometriosis.

Endometriosis is a complex, chronic inflammatory disease in which immune system disorders play an important role. Soluble mediators of the immune and inflammatory response, including cytokines, are involved in these processes. Therefore, the aim of the conducted research was to understand the role of selected cytokines belonging to the Interleukin-1(IL-1) family, including IL-36α, IL-36β, IL-36γ, IL-36R, IL-37 and IL-38, in the onset and development of endometriosis by analysing the concentration of the tested molecules and to determine whether their concentration depends on the stage of the disease. The study group included 60 women who had pelvic endometriosis diagnosed during laparoscopy and subsequently confirmed by histopathology. The reference group consisted of 20 women who had no endometriosis or other pelvic lesions during laparoscopy. Immunoenzymatic assays were used to determine the concentration of the cytokines studied. In the peritoneal fluid of women with endometriosis, a statistically significant increase in the concentrations of all parameters tested was observed: IL-36α, IL-36β, IL-36γ, IL-36R, IL-37 and IL-38. The concentration of these cytokines depended on the severity of the disease. Disturbances of the immune system involving the network of cytokines belonging to the IL-1 family occurring in the peritoneal fluid environment testify to the involvement of these molecules in the development of the disease and are one of many factors involved in the pathogenesis of endometriosis. The use of some of them in the treatment of endometriosis may be a hope for effective causal treatment of this disease, but this requires further, more advanced research.

Serum cytokines and inflammatory proteins in individuals with heroin use disorder: potential mechanistically based biomarkers for diagnosis

Opioid use disorders cause major morbidity and mortality, and there is a pressing need for novel mechanistic targets and biomarkers for diagnosis and prognosis. Exposure to mu-opioid receptor (MOR) agonists causes changes in cytokine and inflammatory protein networks in peripheral blood, and also in brain glia and neurons. Individuals with heroin use disorder (iHUD) show dysregulated levels of several cytokines in the blood. However, there is limited data on a comprehensive panel of such markers in iHUD versus healthy controls (HC), especially considered as a multi-target biomarker. We used a validated proximity extension assay for the relative quantification of 92 cytokines and inflammatory proteins in the serum of iHUD on medication-assisted therapy (MAT; n = 21), compared to HC (n = 24). Twenty-nine targets showed significant group differences (primarily iHUD>HC), surviving multiple comparison corrections (p = 0.05). These targets included 19 members of canonical cytokine families, including specific chemokines, interleukins, growth factors, and tumor necrosis factor (TNF)-related proteins. For dimensionality reduction, data from these 19 cytokines were entered into a principal component (PC) analysis, with PC1 scores showing significant group differences (iHUD > HC; p < 0.0001). A receiver-operating characteristic (ROC) curve analysis yielded an AUROC = 91.7% (p < 0.0001). This PC1 score remained a positive predictor of being in the HUD group in a multivariable logistic regression, that included select demographic/clinical variables. Overall, this study shows a panel of cytokines that differ significantly between iHUD and HC, providing a multi-target “cytokine biomarker score” for potential diagnostic purposes, and future examination of disease severity.

Cytokine dysregulation in amnestic mild cognitive impairment

The pathophysiology of amnestic Mild Cognitive Impairment (aMCI) is largely unknown, although some papers found signs of immune activation. To assess the cytokine network in aMCI after excluding patients with major depression (MDD) and to examine the immune profiles of quantitative aMCI (qMCI) and distress symptoms of old age (DSOA) scores. A case-control study was conducted on 61 Thai aMCI participants and 60 healthy old adults (both without MDD). The Bio-Plex Pro human cytokine 27-plex test kit was used to assay cytokines/chemokines/growth factors in fasting plasma samples. aMCI is characterized by a significant immunosuppression, and reductions in T helper 1 (Th)1 and T cell growth profiles, the immune-inflammatory responses system, interleukin (IL)1β, IL6, IL7, IL12p70, IL13, GM-CSF, and MCP-1. These 7 cytokines/chemokines exhibit neuroprotective effects at physiologic concentrations. In multivariate analyses, three neurotoxic chemokines, CCL11, CCL5, and CXCL8, emerged as significant predictors of aMCI. Logistic regression showed that aMCI was best predicted by combining IL7, IL1β, MCP-1, years of education (all inversely associated) and CCL5 (positively associated). We found that 38.2% of the variance in the qMCI score was explained by IL7, IL1β, MCP-1, IL13, years of education (inversely associated) and CCL5 (positively associated). The DSOA was not associated with any immune data. An imbalance between lowered levels of neuroprotective cytokines and chemokines, and relative increases in neurotoxic chemokines are key factors in aMCI. Future MCI research should always control for the confounding effects of affective symptoms.

Impact of nutrition on wound healing

Whether from an unintentional damage or surgical intervention, wounds require the cooperation of a complex network of blood cells, tissue types, cytokines, and growth hormones to heal. Increased cellular activity as a result leads to a higher metabolic need for nutrients. Inadequate nutrition can delay the healing process, and a number of nutrients needed for wound repair can speed up the healing process. Inflammatory, proliferative, remodelling, and wound closure are the four stages of wound healing. The wound must be cleaned and clot during the inflammatory period. Through tissue growth, the proliferative phase creates the wound bed. Collagen becomes more robust during the remodelling process. Nutritional integrity is essential at all times. Calcium, zinc, vitamins K, A, and E, and proteins are necessary during inflammation. Amino acids, B vitamins, fats, zinc, and iron all have a role in proliferation. However, this review highlights regarding possible roles for nutrition in wound healing.

Полиморфные варианты генов цитокинов в популяциях Арктической зоны России: предрасположенность к заболеваниям

The strategy for the development of the Arctic zone of Russia is primarily aimed at improving the quality of life of the Arctic population, health saving and reducing morbidity. The climatic and geographical conditions of the Arctic zone are extremely uncomfortable for living and cause the development of a number of diseases, as well as the polysyndrome of “northern stress”. Moreover, the Arctic population is affected by persistent organic pollutants that enter the body through a traditional diet and contribute to the development of oncological diseases by suppressing the functions of the immune system. Cytokines — proteins encoded by genes with a high degree of polymorphism, responsible for the nature of inflammatory processes, for the effectiveness of defense functions of the body in response to infections and the oncological process development — are one of the main mediators of the immune system. The distribution of polymorphisms in the cytokine genes produced by different types of cells of immune system (rs2069762 IL2, rs2243250 IL4, rs2069812 IL5, rs1800872 IL10, rs1800925 IL13, rs2275913 IL17A, rs7044343 IL33) in the populations of Nenets, Dolgan-Nganasans and Slavs was studied. Analysis of the results showed that the frequency of TG and GG genotypes rs2069762 IL2, CT genotype rs2243250 IL4, CT genotype rs2069812 IL5, TG genotype rs1800872 IL10, CC genotype rs1800925 IL13, GA genotype rs2275913 IL17A, CC rs7044343 IL33 genotype is significantly higher in Arctic populations compared to Slavs, and may be a potential genetic marker of disease development. The studied mutations are associated with the expression level of the corresponding cytokines and their production, which entails changes in the functioning of the cytokine network. It can be concluded that the indigenous inhabitants of the Russian Arctic have genetically determined rapid development of immune reactions, protection to the development of allergic diseases and resistance to the formation of malignant tumours in comparison with Slavs, i.e. the immigrant population.

Targeting cytokine networks in neuroinflammatory diseases.

In neuroinflammatory diseases, systemic (blood-borne) leukocytes invade the central nervous system (CNS) and lead to tissue damage. A causal relationship between neuroinflammatory diseases and dysregulated cytokine networks is well established across several preclinical models. Cytokine dysregulation is also observed as an inadvertent effect of cancer immunotherapy, where it often leads to neuroinflammation. Neuroinflammatory diseases can be separated into those in which a pathogen is at the centre of the immune response and those of largely unknown aetiology. Here, we discuss the pathophysiology, cytokine networks and therapeutic landscape of 'sterile' neuroinflammatory diseases such as multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), neurosarcoidosis and immune effector cell-associated neurotoxicity syndrome (ICANS) triggered by cancer immunotherapy. Despite successes in targeting cytokine networks in preclinical models of neuroinflammation, the clinical translation of targeting cytokines and their receptors has shown mixed and often paradoxical responses.

Regulatory cytokine network and macrophages (in memory of Irina S. Freidlin)

Irina S. Freidlin was an outstanding Soviet and Russian immunologist, Doctor of Medical Sciences, Professor, Honored Scientist, Corresponding Member of the Russian Academy of Sciences. She was a natural for teaching and a deep scientific researcher whose interests were mainly related to the study of innate immunity.

Relationship of TSH and FT3 Levels to The Incidence of Hashimoto's Thyroiditis in Autoimmune Patients

Hashimoto's thyroiditis is portrayed by the presence of thyroid autoantibodies. Pathogenetic systems, a few cytokine networks have been recognized to be engaged with thyroid cells in a progression of proinflammatory impacts, like the statement of provocative parts, and a progression of imperfections in administrative Lymphocytes that control the deficiency of resistance to thyroid autoantigens, subsequently assuming an immediate part in the autoimmune cycle causing a few diligent side effects. The point of this review was to assess the connection between 36 autoimmune patients matured 14 to 52 years with responsive ANA test results. Then, Thyroid-Animate Hormone (TSH) and free Triiodothyronine (fT3) levels were analyzed utilizing the Enzyme-linked immunosorbent assay (ELISA) technique. The consequences of the review showed that the quantity of ladies was more prominent than men, 32 individuals (88.9%) and 10 individuals matured between 20-25 years. The typical TSH level was 9.65uIU/mL and the free T3 level was 1.64pg/ml. The consequences of the Spearman connection test among TSH and free T3 levels got a worth of p = 0.029 (p&lt;0.05), implying that the connection between TSH levels and the free T3 test had an adequate relationship of - 0.364 (0.260-0.500), however was negative and not in a similar heading, so that when the levels TSH expands, fT3 levels will diminish. All in all, in autoimmune sufferers essential hypothyroidism happens, when the thyroid organ creates low Free T3, causing the deficiency of negative criticism restraint on the front pituitary, bringing about expanded creation of the TSH hormone which causes Hashimoto's thyroiditis.

Unraveling the impact of lysosomal dysfunction on myeloproliferative neoplasm.

Lysosomal dysfunction (LD) impacts cytokine regulation, inflammation, and immune responses, influencing the development and progression of cancer. Inflammation is implicated in the pathogenesis of myeloproliferative neoplasm (MPN). With a hypothesis that LD significantly contributes to MPN carcinogenesis by inducing abnormal inflammation, our objective was to elucidate the pathophysiological mechanisms of MPN arising from an LD background. Genotyping of the LD background was performed in a cohort of MPN patients (n = 190) and healthy controls (n = 461). Logistic regression modeling, utilizing genotype data, was employed to estimate the correlation between LD and MPN. Whole transcriptome sequencing (WTS) (LD carriers = 8, non-carriers = 6) and single-cell RNA sequencing data (LD carriers = 2, non-carriers = 2, healthy controls = 2) were generated and analyzed. A higher variant frequency of LD was observed in MPN compared to healthy controls (healthy, 4.9%; MPN, 7.8%), with the highest frequency seen in polycythemia vera (PV) (odds ratio = 2.33, p = 0.03). WTS revealed that LD carriers exhibited upregulated inflammatory cytokine ligand-receptor genes, pathways, and network modules in MPNs compared to non-carriers. At the single-cell level, there was monocyte expansion and elevation of cytokine ligand-receptor interactions, inflammatory transcription factors, and network modules centered on monocytes. Notably, Oncostatin-M (OSM) consistently emerged as a candidate molecule involved in the pathogenesis of LD-related PV. In summary, an LD background is prevalent in MPN patients and leads to increased cytokine dysregulation and inflammation. OSM, as one of the potential molecules, plays a crucial role in PV pathogenesis by impairing lysosomal function.

Tuning the B-CLL microenvironment: evidence for BAG3 protein- mediated regulation of stromal fibroblasts activity

The Bcl2-associated athanogene-3 (BAG3) protein, a critical regulator of cellular survival, has been identified as a potential therapeutic target in various malignancies. This study investigates the role of BAG3 within stromal fibroblasts and its interaction with B-cell chronic lymphocytic leukemia (B-CLL) cells. Previous research demonstrated that BAG3 maintains the active state of pancreatic stellate cells (PSCs) and aids pancreatic ductal adenocarcinoma (PDAC) spread via cytokine release. To explore BAG3’s role in bone marrow-derived stromal fibroblasts, BAG3 was silenced in HS-5 cells using siRNA. In co-culture experiments with PBMCs from B-CLL patients, BAG3 silencing in HS-5 cells increased apoptosis and decreased phosphorylation of BTK, AKT, and ERK in B-CLL cells, thus disrupting their pro-survival key signaling pathways. The observation of fibroblast-activated protein (FAP) positive cells in infiltrated bone marrow specimens co-expressing BAG3 further support the involvement of the protein in fibroblast-mediated tumor survival. Additionally, BAG3 appears to support B-CLL survival by modulating cytokine networks, including IL-10 and CXCL12, which are essential for leukemic cell survival and proliferation. A robust correlation between BAG3 expression and the levels of CXCL12 and IL-10 was observed in both co-cultures and patient specimens. These findings point out the need for a more in-depth comprehension of the intricate network of interactions within the tumor microenvironment and provide valuable insights for the selection of new potential therapeutic targets in the medical treatment of CLL.

Exploring the Role of Hormones and Cytokines in Osteoporosis Development.

The disease of osteoporosis is characterized by impaired bone structure and an increased risk of fractures. There is a significant impact of cytokines and hormones on bone homeostasis and the diagnosis of osteoporosis. As defined by the World Health Organization (WHO), osteoporosis is defined as having a bone mineral density (BMD) that is 2.5 standard deviations (SD) or more below the average for young and healthy women (T score < -2.5 SD). Cytokines and hormones, particularly in the remodeling of bone between osteoclasts and osteoblasts, control the differentiation and activation of bone cells through cytokine networks and signaling pathways like the nuclear factor kappa-B ligand (RANKL)/the receptor of RANKL (RANK)/osteoprotegerin (OPG) axis, while estrogen, parathyroid hormones, testosterone, and calcitonin influence bone density and play significant roles in the treatment of osteoporosis. This review aims to examine the roles of cytokines and hormones in the pathophysiology of osteoporosis, evaluating current diagnostic methods, and highlighting new technologies that could help for early detection and treatment of osteoporosis.

Major Adverse Cardiovascular Events: The Importance of Serum Levels and Haplotypes of the Anti-Inflammatory Cytokine Interleukin 10.

Cardiovascular diseases (CVDs) represent major medical and socio-economic challenges worldwide. There is substantial evidence that CVD is closely linked to inflammatory changes triggered by a complex cytokine network. In this context, interleukin 10 (IL-10) plays an important role as a pleiotropic cytokine with an anti-inflammatory capacity. In this study (a substudy of ClinTrials.gov, identifier: NCT01045070), the prognostic relevance of IL-10 levels and IL-10 haplotypes (rs1800896/rs1800871/rs1800872) was assessed regarding adverse cardiovascular outcomes (combined endpoint: myocardial infarction, stroke/transient ischemic attack, cardiac death and death according to stroke) within a 10-year follow-up. At baseline, 1002 in-patients with CVD were enrolled. Serum levels of IL-10 were evaluated utilizing flow cytometry (BD™ Cytometric Bead Array). Haplotype analyses were carried out by polymerase chain reactions with sequence-specific primers (PCR-SSP). In a survival analysis, IL-10 haplotypes were not proven to be cardiovascular prognostic factors in a 10-year follow-up (Breslow test: p = 0.423). However, a higher IL-10 level was associated with adverse cardiovascular outcomes (Breslow test: p = 0.047). A survival analysis considering adjusted hazard ratios (HRs) could not confirm this correlation (Cox regression: adjusted HR = 1.26, p = 0.168). In the present study, an elevated IL-10 level but not IL-10 haplotypes was linked to adverse cardiovascular outcomes (10-year follow-up) in a cohort of CVD patients.

Circulating inflammatory cytokines and the risk of sepsis: a bidirectional mendelian randomization analysis

BackgroundSepsis is a life-threatening condition that is characterized by multiorgan dysfunction and caused by dysregulated cytokine networks, which are closely associated with sepsis progression and outcomes. However, currently available treatment strategies that target cytokines have failed. Thus, this study aimed to investigate the interplay between genetically predicted circulating concentrations of cytokines and the outcomes of sepsis and to identify potential targets for sepsis treatment.MethodsData related to 35 circulating cytokines in 31,112 individuals (including 11,643 patients with sepsis) were included in genome-wide association studies (GWASs) from the UK Biobank and FinnGen consortia. A bidirectional two-sample Mendelian randomization (MR) analysis was performed using single nucleotide polymorphisms (SNPs) to evaluate the causal effects of circulating cytokines on sepsis outcomes and other cytokines.ResultsA total of 35 inflammatory cytokine genes were identified in the GWASs, and 11 cytokines, including Interleukin-1 receptor antagonist (IL-1ra), macrophage inflammatory protein 1 (MIP1α), IL-16, et al., were associated with sepsis outcome pairs according to the selection criteria of the cis-pQTL instrument. Multiple MR methods verified that genetically predicted high circulating levels of IL-1ra or MIP1α were negatively correlated with genetic susceptibility to risk of sepsis, including sepsis (28-day mortality), septicaemia, streptococcal and pneumonia-derived septicaemia (P ≤ 0.01). Furthermore, genetic susceptibility of sepsis outcomes except sepsis (28-day mortality) markedly associated with the circulating levels of five cytokines, including active plasminogen activator inhibitor (PAI), interleukin 7 (IL-7), tumour necrosis factor alpha (TNF-α), beta nerve growth factor (NGF-β), hepatic growth factor (HGF) (P < 0.05). Finally, we observed that the causal interaction network between MIP1α or IL-1ra and other cytokines (P < 0.05).ConclusionsThis comprehensive MR analysis provides insights into the potential causal mechanisms that link key cytokines, particularly MIP1α, with risk of sepsis, and the findings suggest that targeting MIP1α may be a potential strategy for preventing sepsis.

Secreted chemokines reveal diverse inflammatory and degenerative processes in the intervertebral disc of the STZ-HFD mouse model of Type 2 diabetes.

The chronic inflammation present in type 2 diabetes causes many chronic inflammatory comorbidities, including cardiovascular, renal, and neuropathic complications. Type 2 diabetes is also associated with a number of spinal pathologies, including intervertebral disc (IVD) degeneration and chronic neck and back pain. Although confounding factors such as obesity are thought to increase the loads to the musculoskeletal system and subsequent degeneration, studies have shown that even after adjusting age, body mass index, and genetics (e.g. twins), patients with diabetes suffer from disproportionately more IVD degeneration and back pain. Yet the tissue-specific responses of the IVD during diabetes remains relatively unknown. We hypothesize that chronic diabetes fosters a proinflammatory microenvironment within the IVD that accelerates degeneration and increases susceptibility to painful disorders. To test this hypothesis, we evaluated two commonly used mouse models of diabetes - the leptin-receptor deficient mouse (db/db) and the chronic high-fat diet in mice with impaired beta-cell function (STZ-HFD). The db/db is a genetic model that spontaneous develop diabetes through hyperphagia, while the STZ-HFD mouse first exhibits rapid obesity development under HFD and pronounced insulin resistance following streptozotocin administration. Both animal models were allowed to develop sustained diabetes for at least twelve weeks, as defined by elevated hemoglobin A1C, hyperglycemia, and glucose intolerance. Following the twelve-week period, the IVDs were extracted in quantified in several measures including tissue-specific secreted cytokines, viscoelastic mechanical behavior, structural composition, and histopathologic degeneration. Although there were no differences in mechanical function or the overall structure of the IVD, the STZ-HFD IVDs were more degenerated. More notably, the STZ-HFD model shows a significantly higher fold increase for eight cytokines: CXCL2, CCL2, CCL3, CCL4, CCL12 (monocyte/macrophage associated), IL-2, CXCL9 (T-cell associated), and CCL5 (pleiotropic). Correlative network analyses revealed that the expression of cytokines differentially regulated between the db/db and the STZ-HFD models. Moreover, the STZ-HFD contained a fragmented and modular cytokine network, indicating greater complexities in the regulatory network. Taken together, the STZ-HFD model of type 2 diabetes may better recapitulate the complexities of the chronic inflammatory processes in the IVD during diabetes.