Influence Of Proinflammatory Cytokines Research Articles

Proinflammatory Cytokines Enhance the Mineralization, Proliferation, and Metabolic Activity of Primary Human Osteoblast-like Cells.

Osteoporosis is a progressive metabolic bone disease characterized by decreased bone density and microarchitectural deterioration, leading to an increased risk of fracture, particularly in postmenopausal women and the elderly. Increasing evidence suggests that inflammatory processes play a key role in the pathogenesis of osteoporosis and are strongly associated with the activation of osteoclasts, the cells responsible for bone resorption. In the present study, we investigated, for the first time, the influence of proinflammatory cytokines on the osteogenic differentiation, proliferation, and metabolic activity of primary human osteoblast-like cells (OBs) derived from the femoral heads of elderly patients. We found that all the proinflammatory cytokines, IL-1β, TNF-α, IL-6, and IL-8, enhanced the extracellular matrix mineralization of OBs under differentiation-induced cell culture conditions. In the cases of IL-1β and TNF-α, increased mineralization was correlated with increased osteoblast proliferation. Additionally, IL-1β- and TNF-α-increased osteogenesis was accompanied by a rise in energy metabolism due to improved glycolysis or mitochondrial respiration. In conclusion, we show here, for the first time, that, in contrast to findings obtained with cell lines, mesenchymal stem cells, or animal models, human OBs obtained from patients exhibited significantly enhanced osteogenesis upon exposure to proinflammatory cytokines, probably in part via a mechanism involving enhanced cellular energy metabolism. This study significantly contributes to the field of osteoimmunology by examining a clinically relevant cell model that can help to develop treatments for inflammation-related metabolic bone diseases.

HERV-E ƛ 4-1 activation in peripheral blood mononuclear cells of the recurrent depression patients under the influence of human recombinant IL-1β

IntroductionMental disorders represent complex phenotypes and are the leading causes of global disease burden. Human endogenous retroviruses (HERVs) are ancient retroviral DNA sequences established into germline. Their tight regulation is mainly achieved by epigenetic mechanisms, which can be altered by environmental factors - viral infections, inflammation, leading to HERV activation. The aberrant expression of HERVs associates with neurological diseases and mood disorders. We showed earlier that HERV-E ƛ 4-1 activation is associated with the recurrent depression stage of exacerbation and are accompanied by a pronounced increase in the proinflammatory activity of the peripheral blood mononuclear cells (PBMC).ObjectivesThe purpose of the study was to evaluate the activity of HERV-E ƛ 4-1 on PBMCs of patients with recurrent depression in remission, including under the influence of recombinant human IL-1β.MethodsThe study included 30 patients with an established diagnosis of recurrent depression (F 33.0) aged 26–45 years. PBMC were isolated using the Ficoll density gradient method and further cultured in the presence or absence of 1 mkg/ml of recombinant human IL-1β for 24 hours. HERV-E λ 4 – 1 env gene expression was determined by the PCR. Cells proliferative activity was determined by H3-thymidine incorporation. Cytokines content in culture supernatants was assessed by ELISA.ResultsIt was shown that in all samples of PBMC cultured without IL-1β the HERV-E λ 4 – 1 env expression was not determined. After the PBMC cocultivation with recombinant human IL-1β, HERV-E λ 4 – 1 env gene expression was determined in 86,7% of cases. The HERV-E ƛ 4-1 activation in PBMC after IL-1β influence was accompanied by increased cells proliferative activity and production of IL-1β, IL-6.ConclusionsOur data indicate that the HERV-E λ 4 – 1 env expression in PBMC of recurrent depression patients in the stage of remission induced by the influence of proinflammatory cytokines, such as IL-1β. This mechanism may be one of the possible regulators of HERV-E λ 4 – 1 activation in recurrent depression.Disclosure of InterestNone Declared

Longitudinal Patient Analysis Suggests a Positive Correlation of IL-10/IL-6 and FVIII Inhibitor Amount

Hemophilia A (HA) is the most common X-linked bleeding disorder caused by a deficiency in coagulation factor VIII (FVIII). Inhibitor development in up to 30% of HA patients is the most challenging complication in HA treatment and has been associated with several patient-related risk factors such as gene mutation and residual plasma factor VIII concentrations. Treatment related risk factors are under debate. However, HCV infections were recently shown to correlate with low level inhibitor abundance, potentially as a result of chemokine and cytokine regulation. Therefore, the aim of this study was to evaluate a potential connection between proinflammatory cytokine levels and FVIII-specific B cell responses in HA patients without infections, but with other comorbidities that might modulate cytokine levels. Thus, several clinical parameters and concentrations of plasmatic proinflammatory cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-12p70, TNF, IFNa, IFNg, TNFa, MCP-,1 IL-17A, IL-18, IL-23 and IL-33) were quantified from different patient samples. At first, the influence of proinflammatory cytokines on inhibitor development was assessed in a HA patient, who had an intron 22 inversion and was also diagnosed with type 1 diabetes. Prophylactic treatment began at the age of 9 months with 30IU/kg Octanate, and after four days of exposure, the formation of inhibitors was initially detected. Longitudinal cytokine analysis in plasma samples of that patient revealed differential regulation patterns of cytokines. IL-1b, IFNg, TNFa, IL-6, IL-10 and IL-12p70 tended to increase upon inhibitor occurrence, whereas other cytokines remained unchanged (MCP-1, IL-8, IL-17A, IL-18 and IL-23) or decreased (IFNa2 and IL-33). Next, a correlation analysis was performed, assuming that proinflammatory cytokines might stimulate B cells to produce antibodies. This analysis involved all cytokines that were found to be elevated upon inhibitor formation. The comparison of clinical and laboratory data from that patient revealed a strong association of inhibitor levels and IL-10 expression (Pearson r = 0,9391; R squared = 0,8818) as well as with IL-6 (Pearson r = 0,9290; R squared = 0,8630). Furthermore, a modest correlation was observed for IL-1b (Pearson r = 0,5277; R squared = 0,2785), IFNg (Pearson r = 0,3413; R squared = 0,1165), IL-12p70 (Pearson r = 0,3547; R squared = 0,1258), and TNFa (Pearson r = 0,3070; R squared = 0,09422). Other proinflammatory cytokines with a rather stable profile upon inhibitor initiation like MCP-1 (Pearson r = -0,06810; R squared = 0,004638) and IL-18 (Pearson r = 0,2245; R squared = 0,05042) seemed not to be directly correlated with inhibitor occurrence. Finally, we aim to investigate the potential impact of IL-10 and IL-6 on inhibitor production and/or FVIII immune tolerization across various patient groups and conditions. Therefore, we will compare patients with detectable inhibitor titers, those who have successfully eradicated inhibitors, and individuals without inhibitor titers (with normal recovery). Preliminary data suggest a positive correlation between both cytokines and active inhibitor presence. However, to reach a definitive conclusion, the sample size will be/should be increased.

Examining the influence of inflammatory bowel disease medications on sleep quality.

Inflammatory bowel disease (IBD) can disrupt sleep, leading to poor sleep quality. This may in part be due to the symptoms of IBD and the influence of pro-inflammatory cytokines on sleep. This study aimed to investigate the potential influence of IBD medications on sleep quality. An online survey of adults with IBD was conducted, which included measures of sleep quality, IBD activity, anxiety, depression, and physical activity. Logistic regression was used to investigate possible associations between IBD medications (corticosteroids, immunomodulators, biologics, aminosalicyate) and outcome of poor sleep. A generalized linear model was built for outcome of sleep quality score. There were 544 participants included in the final analysis, median age of 42, and 61% with Crohn's disease. Increased odds of poor sleep were seen in those taking opioids, medications for anxiety or depression, corticosteroids, vitamin D, methotrexate, and infliximab. A multivariate model was built incorporating demographic and IBD variables with opioids present in the final model and associated with increased odds of poor sleep. This was in addition to medications for sleep, depression, anxiety, IBD activity, and body weight. In a multivariate generalized linear model, opioids and methotrexate were associated with worse sleep quality scores. Opioids were associated with increased odds of poor sleep independent of other factors. This provides further support for avoiding these medications in people with IBD. Infliximab was associated with increased body weight and consequently increased odds of poor sleep.

Determination of pro-inflammatory and humoral factors in gonarthrosis in women with hypertension and overweight

Purpose of the study. The purpose of the work. to study the influence of pro-inflammatory cytokines and neurohumoral factors of adipose tissue on the pathogenesis of HA in women with NM and hypertension to further improve the effectiveness of treatment of this group of patients.
 Materials and methods. We examined 198 women with GA and GA in combination with GC and NM aged 40 to 70 years (average - 62.6 ± 1.9 years) with a disease duration of an average of 13.4 ± 3.8 years. In order to analyze the impact of comorbid pathology on the underlying disease, all surveyed women were divided into three groups. The first group (G1) included 59 women with symptoms of HA without concomitant pathology, the second (G2) group - 74 women with HA and GC, and the third (G3) 65 women with HA and GC and NM. All patients underwent standard general clinical examination. In order to study the neurohumoral aspects of the disease, enzyme-linked immunosorbent assay of C-reactive protein, tumor necrosis factor, interleukin-1beta, interleukin 6, interleukin 10 and leptin was performed.
 Results. It was found that the combination of excess weight with the course of HA leads to a more significant increase in the production of proinflammatory cytokines compared with patients with HA without concomitant pathology (p <0.05). Direct correlations have been established between weight gain and increased levels of proinflammatory cytokines and adipose tissue neurohumoral factors.
 Conclusions. The combination of inflammatory and destructive changes in the joints in HA with weight gain and increased blood pressure, creates conditions for the development of severe immunological disorders in patients and requires pharmacological correction.

Increased inflammatory response is associated with less favorable functional results 5 years after total knee arthroplasty

PurposeAllergy against implant materials is discussed controversially and still not fully understood. Despite these controversies, a relevant number of patients receive hypoallergenic knee implants. The aim of this study was to compare a new coating system with the standard implant in total knee arthroplasty (TKA). Additionally, the influence of proinflammatory cytokines on patient-reported outcome measures (PROMs) was investigated.Methods120 patients without known metal allergy and without previous metal implants were included. The patients were randomized to receive a coated or standard TKA of the same knee system. 105 patients completed the 5 year follow-up. Patient-reported outcome measures (PROMs) including knee function (Oxford Knee Score, OKS), quality of life (SF36) and UCLA activity scale were assessed. Additionally, several cytokines with a possible role in implant allergy were measured in patient`s serum (IL-1beta, IL-5, IL-6, IL-8, IL-10, IP-10, IFN γ, TNF α). Group comparison was performed using Mann–Whitney U test for continuous values and chi-square test for categorical values.ResultsThere were no differences in PROMs between both groups at any follow-up. The majority of patients demonstrated no elevation of the measured blood cytokines. The blood cytokine pattern after 5 years demonstrated no differences between study groups. There was a significant association between elevated IL-8 values and worse results in the overall OKS (p = 0.041), the OKS function component (p = 0.004), the UCLA activity scale (p = 0.007) and the physical component of SF36 (p = 0.001).ConclusionThere were no problems with the new coating during mid-term follow-up and no differences in PROMs between coated and standard TKA. Patients with an increased inflammatory response demonstrated worse functional results, regardless of the implant.Level of evidenceI.Clinical trial registrationThe study protocol was registered in the US National Institutes of Health’s database (http://www.clinicaltrials.gov) registry under NCT00862511.

Immunological Effects of an Add-On Physical Exercise Therapy in Depressed Adolescents and Its Interplay with Depression Severity.

Background: Pro-inflammatory cytokines (PICs) have gained attention in the pathophysiology and treatment of depressive disorders. At the same time, the therapeutic effect of physical activity seems to work via immunomodulatory pathways. The interventional study “Mood Vibes” analyzed the influence of exercise on depression severity (primary endpoint) in depressive adolescents; the influence of PICs on the clinical outcome was analyzed as a secondary endpoint. Methods: Clinically diagnosed depressed adolescents (N = 64; 28.1% male; mean age = 15.9; mean BMI = 24.6) were included and participated either in Whole Body Vibration (WBV) (n = 21) or bicycle ergometer training (n = 20) in addition to treatment-as-usual (TAU). Patients in the control treatment group received TAU only (n = 23). The PICs (interleukin-6—IL-6 and tumor necrosis factor-α—TNF-α) were analyzed before intervention, after 6 weeks of training (t1), and 8 weeks post-intervention (t2). The effects of the treatment on depression severity were rated by self-rating “Depression Inventory for Children and Adolescents” (DIKJ). Results: Basal IL-6 decreased in all groups from t0 to t1, but it increased again in WBV and controls at t2. TNF-α diminished in ergometer and controls from baseline to t1. PIC levels showed no correlation with depression severity at baseline. The influence on DIKJ scores over time was significant for IL-6 in the WBV group (p = 0.008). Sex had an impact on TNF-α (p < 0.001), with higher concentrations in male patients. Higher body mass index was associated with higher IL-6 concentrations over all measurement points (p < 0.001). Conclusions: The positive effects of an intensive add-on exercise therapy on adolescent depression seem to be partly influenced by immunomodulation. A small sample size and non-randomized controls are limitations of this study.

Mechanisms of Reciprocal Regulation of Gonadotropin-Releasing Hormone (GnRH)-Producing and Immune Systems: The Role of GnRH, Cytokines and Their Receptors in Early Ontogenesis in Normal and Pathological Conditions

Different aspects of the reciprocal regulatory influence on the development of gonadotropin-releasing hormone (GnRH)-producing- and immune systems in the perinatal ontogenesis and their functioning in adults in normal and pathological conditions are discussed. The influence of GnRH on the development of the immune system, on the one hand, and the influence of proinflammatory cytokines on the development of the hypothalamic-pituitary-gonadal system, on the other hand, and their functioning in adult offspring are analyzed. We have focused on the effects of GnRH on the formation and functional activity of the thymus, as the central organ of the immune system, in the perinatal period. The main mechanisms of reciprocal regulation of these systems are discussed. The reproductive health of an individual is programmed by the establishment and development of physiological systems during critical periods. Regulatory epigenetic mechanisms of development are not strictly genetically controlled. These processes are characterized by a high sensitivity to various regulatory factors, which provides possible corrections for disorders.

Tuning Thermal Dosage to Facilitate Mesenchymal Stem Cell Osteogenesis in Pro-Inflammatory Environment.

Mesenchymal stem cells (MSCs) are multipotent cells that can replicate and differentiate to different lineages, potentiating their use as integral components in regenerated mesenchymal tissues. Our previous work and other studies have indicated that mild heat shock enhances osteogenesis. However, the influence of pro-inflammatory cytokines on osteogenic differentiation during mildly elevated temperature conditions remains to be fully explored. In this study, human MSCs (hMSCs) were cultured with tumor necrosis factor-alpha (TNF-α), an important mediator of the acute phase response, and interleukin-6 (IL-6) which plays a role in damaging chronic inflammation, then heat shocked at 39 °C in varying frequencies-1 h per week (low), 1 h every other day (mild), and 1 h intervals three times per day every other day (high). DNA data showed that periodic mild heating inhibited suppression of cell growth caused by cytokines and induced maximal proliferation of hMSCs while high heating had the opposite effect. Quantitative osteogenesis assays show significantly higher levels of alkaline phosphatase (ALP) activity and calcium precipitation in osteogenic cultures following mild heating compared to low heating or nonheated controls. These results demonstrate that periodic mild hyperthermia may be used to facilitate bone regeneration using hMSCs, and therefore may influence the design of heat-based therapies in vivo.

The Influence of Pro-inflammatory Cytokines and Genetic Variants in the Development of Fibromyalgia: A Traditional Review

Fibromyalgia is a complex syndrome characterized by widespread chronic pain, without any obvious etiology, and it is often accompanied by a constellation of symptoms such as fatigue, sleep disturbances and cognitive dysfunction, to name a few. The syndrome may be associated with a variety of autoimmune and psychiatric conditions. Fibromyalgia can occur with other musculoskeletal pathologies and its symptoms can overlap with other chronic painful conditions such as chronic myofascial pain syndromes seen in cervical and lumbar spinal osteoarthritis and degenerative disc disease. Gene polymorphisms have been related to a decreased pain threshold and an increased susceptibility to disorders associated with chronic pain. Some of those genetic variants might trigger the onset of fibromyalgia. Researchers are looking into the possible factors that might contribute to its pathophysiology. It is important to study the connections between pro-inflammatory cytokines and genetic variants in pain-related genes and their roles in predisposition and development of fibromyalgia. The objective of this review article is to provide a brief overview of the pro-inflammatory cytokines commonly associated with fibromyalgia, as well as to look into the genes that have shown some level of involvement in the development of fibromyalgia and its symptomatology.

Potential Ways to Increase Body Resistance to Damaging Action of Ionizing Radiation with Radiomitigators

This review considers the potential mechanisms of radiomitigative effect of radioprotective drugs in interaction with pathophysiological processes accompanying radiation injury to tissues at the earliest stages of its development. Radiomitigators affect bodily systems throughout the development of primary radiation stress and inflammatory process upon the realization of radiation injury during the primary radiation reaction. Inflammation as a protective body reaction to pathogens represents a self-organized system that commits support and limits the intensity of its manifestation. For this reason, the implementation of the radioprotective effect of radiomitigators, including immunogens, proinflammatory cytokines, steroid hormones, biogenic amines, and purine nucleosides and their synthetic and natural analogs, which stimulate native immunity, depends on its initial state and the severity of radiation injury of the body. The inverse negative relation in response to the action of proinflammatory cytokines, which is manifested as induction of the synthesis of anti-inflammatory cytokines and hematopoietic growth factors (primarily, granulocyte colony–stimulating factor), promotes the activation of myelopoiesis and their antiapoptotic action. The interaction of the immunogen effect and radiation stress depends on pharmacodynamics and features of the realization of the radioprotective properties of drugs. The implementation of the action of radiomitigators depends on the functioning of the antioxidant system of the body, because it can be exhausted under the influence of inflammation. In this case, postradiation oxidative toxemia induces injuries to vital parenchymatous organs. This is observed under the influence of proinflammatory cytokines at combined radiation injuries. All of the listed groups of radiomitigators have identical radioprotective activity (DRF = 1.2–1.3). The absence of expressed side effects, good tolerance of radiomitigators by humans, and the duration of their possible effective application after irradiation are the key indices for assessment of their prospects in radiation accidents.

Pomegranate peel polyphenols inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4/NF-κB pathway activation.

BackgroundsInflammatory response mediated by activated immune cells is a vital process in host defense system while responding to various stresses. Our previous studies have indicated that pomegranate peel polyphenols (PPPs) and their main components punicalagin (PC) and ellagic acid (EA) decreased pro-inflammatory cytokines and inflammatory mediators by regulating the mitogen-activated protein kinases (MAPKs) pathway, but whether these tested polyphenols play an important role in NF-κB signaling pathway, another crucial pathway of inflammation, remains unclear.ObjectiveIn this study, we analyzed the anti-inflammatory effect of these polyphenols via TLR4-NF-κB pathway in lipopolysaccharide (LPS)-induced RAW264.7 macrophages.MethodsDifferent concentrations of PPPs, PC, and EA were pre-incubated with RAW264.7 macrophages and then stimulated with LPS (1 μg/mL), and the effects of reactive oxygen species and TLR4 were investigated. Moreover, NF-κB p65 nuclear translocation and phosphorylation, and degradation of IκB were measured by Western blot. Furthermore, the influence of pro-inflammatory cytokines was detected by enzyme-linked immunosorbent assay (ELISA).ResultsOur data showed that PPPs, PC, and EA inhibited LPS-induced intracellular ROS production and suppressed the mRNA and protein expression levels of TLR4 in a dose-dependent manner. Moreover, the anti-inflammatory mechanism was involved in blocking LPS-induced phosphorylation, degradation of IκB, and nuclear translocation of p65. Additionally, PPPs and PC exhibited a stronger anti-inflammatory effect than that of EA.ConclusionThe results indicated that PPPs possess potent anti-inflammatory effect, and PC was the main effective component in PPPs, which provided new insights into the utilization of PPPs to prevent inflammation-associated disorders.

The Influence of Proinflammatory Cytokines on Voriconazole Trough Concentration in Patients With Different Forms of Hematologic Disorders.

Even though multiple factors are involved in the high fluctuation of voriconazole (VCZ) plasma concentration, little is known regarding the influence of proinflammatory cytokines on VCZ concentration. The aim of this study was to investigate the influence of proinflammatory cytokines, namely, interleukin (IL)-1β, IL-6, IL-18, interferon-γ, tumor necrosis factor-α, and transforming growth factor (TGF)-β1 on VCZ trough concentration (VCZ-Cmin ) in Chinese patients with different forms of hematologic disorders. A total of 250 plasma samples from 113 patients were analyzed for VCZ-Cmin and proinflammatory cytokines using a validated liquid chromatography-tandem mass spectrometry and enzyme-linked immunosorbent assay methods, respectively. Patient demographics and clinical characteristics were obtained from hospital records. VCZ-Cmin was significantly correlated with IL-18 in acute myeloid leukemia (r = 0.456; P ˂ .0001), acute lymphoblastic leukemia (r = 0.317; P = .019), and chronic myeloid leukemia (r = 0.737; P = .004) while VCZ-Cmin and TGF-β1 were correlated (r = 0.436; P ˂ .001) in acute myeloid leukemia patients only. VCZ-Cmin at different concentration range showed significant inhibitory effect of IL-6. A backward multiple linear regression model revealed patient age (coefficient [β] = 0.025; P = .04), gamma-glutamyl transferase (β = 0.003; P = .023), IL-6 (β = -0.001; P = .024), proton pump inhibitor coadministration (β = 1.518; P = .002), and cytochrome P450 (CYP) 2C19 polymorphism as predictors of VCZ-Cmin ; however, these factors explained only 29% of VCZ-Cmin variation. In conclusion, IL-18 and TGF-β1 have correlation with VCZ-Cmin in Chinese patients with leukemia. Apparently, VCZ may have an inhibitory effect on IL-6 levels. Furthermore, patient age, gamma-glutamyl transferase, IL-6, PPI coadministration, and cytochrome P450 2C19 polymormorphism partially predicted the VCZ-Cmin . Therapeutic drug monitoring of VCZ in Chinese patients is highly encouraged.

Pro-inflammatory cytokines enhance dilatation of bile canaliculi caused by cholestatic antibiotics

Many drugs can induce liver injury, characterized by hepatocellular, cholestatic or mixed hepatocellular-cholestatic lesions. While an inflammatory stress is known to aggravate hepatocellular injury caused by some drugs much less evidence exists for cholestatic features. In this study, the influence of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α), either individually or combined, on cytotoxic and cholestatic properties of antibiotics was evaluated using differentiated HepaRG cells. Six antibiotics of various chemical structures and known to cause cholestasis and/or hepatocellular injury in clinic were investigated. Caspase-3 activity was increased with all these tested hepatotoxic drugs and except with erythromycin, was further augmented in presence of cytokines mainly when these were co-added as a mixture. TNF-α and IL-1β aggravated cytotoxicity of TVX more than IL-6. Bile canaliculi (BC) dilatation induced by cholestatic drugs was increased by co-treatment with IL-6 and IL-1β but not with TNF-α. Reduced accumulation of carboxy-dichlorofluorescein, a substrate of the multi-drug resistance-associated protein 2, in antibiotic–induced dilatated BC, was further extended in presence of individual or mixed cytokines. In conclusion, our data demonstrate that pro-inflammatory cytokines either individually or in mixture, can modulate cholestatic and/or cytotoxic responses to antibiotics and that the extent of these effects is dependent on the cytokine and the cholestatic antibiotic.

Immunomodulatory Properties of Bone Marrow Mesenchymal Stem Cells from Patients with Amyotrophic Lateral Sclerosis and Healthy Donors.

Pathogenesis of amyotrophic lateral sclerosis (ALS) involves several mechanisms resulting in a shift from a neuroprotective to a neurotoxic immune reaction. A promising tool for ALS treatment is represented by mesenchymal stem cells (MSCs), which possess both regenerative potential and immunomodulatory properties. In this study, we aimed to compare the immunomodulatory properties of MSCs isolated from the bone marrow of patients suffering from ALS and healthy donors. Moreover, the influence of proinflammatory cytokines on the immunoregulatory functions of MSCs was also evaluated. We found that MSCs from ALS patients and healthy donors comparably affected mitogen-stimulated peripheral blood mononuclear cells and reduced the percentage of T helper (Th)1, Th17 and CD8+CD25+ lymphocytes. These MSCs also equally increased the percentage of Th2 and CD4+FOXP3+ T lymphocytes. On the other hand, MSCs from ALS patients decreased more strongly the production of tumour necrosis factor-α than MSCs from healthy donors, but this difference was abrogated in the case of MSCs stimulated with cytokines. Significant differences between cytokine-treated MSCs from ALS patients and healthy donors were detected in the effects on the percentage of CD8+CD25+ and CD4+FOXP3+ T lymphocytes. In general, treatment of MSCs with cytokines results in a potentiation of their effects, but in the case of MSCs from ALS patients, it causes stagnation or even restriction of some of their immunomodulatory properties. We conclude that MSCs from ALS patients exert comparable immunomodulatory effects to MSCs from healthy donors, but respond differently to stimulation with proinflammatory cytokines. Graphical Abstract Treatment of mesenchymal stem cells (MSCs) with cytokines results in a potentiation of their effects, but in the case of MSCs from amyotrophic lateral sclerosis (ALS) patients, it causes stagnation (an equal reduction of the percentage of CD8+CD25+ T lymphocytes) or even restriction (no increase of proportion of CD4+FOXP3+ T lymphocytes) of some of their immunomodulatory properties. It means that MSCs from ALS patients exert comparable immunomodulatory effects to MSCs from healthy donors, but respond differently to stimulation with proinflammatory cytokines.

Role of nesfatin-1 in the metabolism of skeletal tissues

NUCB2/nesfatin-1, a member of the adipokine family, is a peptide hormone with pleiotropic action. It has been found in different tissues, including cartilage and bone cells. Nesfatin-1 is produced by chondrocytes, and its synthesis increases with the degree of cell differentiation and upon stimulation by pro-inflammatory cytokines, as shown in an in vitro study. An increase in serum levels of nesfatin-1 has been observed in humans with osteoarthritis, which indicates the influence of pro-inflammatory cytokines on nesfatin-1 release. On the other hand, nesfatin-1 stimulates the synthesis of pro-inflammatory cytokines by chondrocytes, which suggests its participation, together with other adipokines, in the pathogenesis and/or progression of inflammatory complications of cartilage degenerative diseases. Nesfatin-1 also promotes pre-osteoblastic cell differentiation and mineralization and inhibits macrophage differentiation towards osteoclasts. Moreover, exogenous nesfatin-1 given to ovariectomized rats reduces osteopenic changes. Therefore, it seems that nesfatin-1 may play a protective role in cartilage and bone diseases. However, further studies are required to determine whether nesfatin-1 can be used for monitoring and treatment of cartilage and bone diseases..

Interleukins 12 and 15 induce cytotoxicity and early NK-cell differentiation in type 3 innate lymphoid cells.

Type 3 innate lymphoid cells (ILC3s) fulfill protective functions at mucosal surfaces via cytokine production. Although their plasticity to become ILC1s, the innate counterparts of type 1 helper T cells, has been described previously, we report that they can differentiate into cytotoxic lymphocytes with many characteristics of early differentiated natural killer (NK) cells. This transition is promoted by the proinflammatory cytokines interleukin 12 (IL-12) and IL-15, and correlates with expression of the master transcription factor of cytotoxicity, eomesodermin (Eomes). As revealed by transcriptome analysis and flow cytometric profiling, differentiated ILC3s express CD94, NKG2A, NKG2C, CD56, and CD16 among other NK-cell receptors, and possess all components of the cytotoxic machinery. These characteristics allow them to recognize and kill leukemic cells with perforin and granzymes. Therefore, ILC3s can be harnessed for cytotoxic responses via differentiation under the influence of proinflammatory cytokines.

Concentration of Transforming Growth Factor-beta 1 in Chronic Periapical Lesions / Ispitivanje koncentracije transformišućeg faktora rasta beta 1 u hroničnim periapeksnim lezijama

Summary Host response to antigen stimulation in chronic inflammatory periapical lesions is mainly controlled by the balance between proinflammatory and anti-inflammatory cytokines. The aim of this study was to determine the concentration of TGF-β1 in the tissue homogenates of periapical lesions and to analyse its level in relation to the symptomatology of the patients and size of the lesions. Ninety three samples of chronic periapical lesions were obtained after extraction of teeth. Samples were divided according to the clinical symptoms as symptomatic and asymptomatic, and according to the size as large and small. The concentration of TGF-β1 was analyzed using ELISA. The results showed increased production of TGF-β1 in symptomatic lesions compared to asymptomatic, but the difference was not statistically significant. Statistically significant difference in TGF-β1 concentrations was observed in large lesions compared to small (p&lt;0,001). It seems that TGF-β1 have a modulating effect on bone tissue resorption activity under the influence of proinflammatory cytokines and can be molecular prognostic marker of periapical lesion healing.

Anemia in children with JIA: is it really driven by hepcidin level, or by a set of factors of a chronic disease

Hepcidin - 25-amino acid peptide - is known to be a key regulator of systemic iron metabolism [Ganz T., Nemeth E., 2012]. Hepcidin acts indirectly through ferroportin, which is both a receptor for hepcidin and the only known exporter of iron in the human body [De Falco L. et. al., 2013]. Hyperproduction of hepcidin due to the influence of pro-inflammatory cytokines, especially IL-6, triggers to transport of iron from circulation to the storage, consequently, limiting iron accessibility for erythropoiesis [Weiss G., Goodnought T., 2005]. Thus, overproduction of hepcidin seems to be the leading mechanism of development of anemia in children with Juvenile Idiopathic Arthritis (JIA). A set of negative factors of a chronic disease, particularly disbalance of vitamins, proteins, amino acids and minerals, which are also the known causes, of anemia can weaken control of iron metabolism by hepcidin.

Neurocysticercosis: the effectiveness of the cysticidal treatment could be influenced by the host immunity.

Neurocysticercosis, a clinically and radiologically pleomorphic parasitic disease, is still endemic to most non-developed countries of Latin America, Africa, and Asia. Anti-helminthic drugs (AHD) are generally effective and rapidly destroy parenchymal cysticerci. In contrast, several cycles of AHD are frequently necessary to damage extraparenchymally located parasites. The present study was designed to evaluate whether differences in the immunological profile of the patients is involved in the diversity of the response to AHD. To this end, a global gene expression microarray and a cytokine analysis were made. Responder patients were those showing a radiological reduction greater than 50% in the parasite burden following AHD treatment. Microarray pre- and post-treatment comparisons showed that a total of eighteen immune-related genes were up-regulated in the five responder patients with respect the expression profile seen in the four non-responder subjects. The function of up-regulated genes exerted pro-inflammatory (RORγC, Sema4A, SLAMF3, SLAMF6), anti-inflammatory (TGFβ, TNFRSF25, TNFRS18, SLAMF1, ILF2), or immunomodulatory effects (CXCL2, RUNX3, SLAMF9, TGFBR3). To further explore the causes of the heterogeneity in the response to treatment, a wide ELISA cytokine analysis was performed in serum, PBMC supernatants, and CSF samples from 39 responder and 26 non-responder patients. Responder patients showed higher CSF IL-17A levels (P=0.04) and higher supernatant IL-6 levels (P=0.03) 60days after treatment. These results suggest a possible influence of pro-inflammatory cytokines on the response to AHD as observed by radiological methods, and thus the possible participation of the host immunity in the effectiveness of AHD treatment.