Proinflammatory cytokines and their inhibitors are involved in the regulation of multiple immune reactions including response to transplanted organs. In this prospective study, we evaluated changes in serum concentrations of six IL-1 family cytokines (IL-1 alpha, IL-1 beta, IL-1RA, IL-18, IL-18BP, and IL-36 beta) in 138 kidney allograft recipients and 48 healthy donors. Samples were collected before transplantation and then after one week, three months and one year, additional sera were obtained at the day of biopsy positive for acute rejection. We have shown, that concentrations of proinflammatory members of the IL-1 family (IL-1β, IL-18, IL-36 β) and anti-inflammatory IL-18BP decreased immediately after the transplantation. The decline of serum IL-1RA and IL-1α was not observed in subjects with acute rejection. IL-18, including specifically its free form, is the only cytokine which increase serum concentrations in the period between one week and three months in both groups of patients without upregulation of its inhibitor, IL-18BP. Serum concentrations of calculated free IL-18 were upregulated in the acute rejection group at the time of acute rejection. We conclude that IL-1 family cytokines are involved mainly in early phases of the response to kidney allograft. Serum concentrations of free IL-18 and IL-18BP represent possible biomarkers of acute rejection, and targeting IL-18 might be of therapeutic value.

• Klíčová slova
• Acute rejection, Allograft, Cytokines, IL-1 family, Kidney, Transplantation,
• Publikační typ
• časopisecké články MeSH

The loss of control of cell proliferation, apoptosis regulation and contact inhibition leads to tumor development. While benign tumors are restricted to their primary space, i.e. where these tumors first originate, the metastatic tumors not only disseminate- facilitated by hypoxia-driven neovascularization- to distant secondary sites but also show substantial changes in metabolism, tissue architectures, gene expression profiles and immune phenotypes. All these alterations result in radio-, chemo- and immune-resistance rendering these metastatic tumor cells refractory to therapy. Since the beginning of the transformation, these factors- which influence each other- are incorporated to the developing and metastasizing tumor. As a result, the complexities in the heterogeneity of tumor progressively increase. This space-time function in the heterogeneity of tumors is generated by various conditions and factors at the genetic as well as microenvironmental levels, for example, endogenous retroviruses, methylation and epigenetic dysregulation that may be etiology-specific, cancer associated inflammation, remodeling of the extracellular matrix and mesenchymal cell shifted functions. On the one hand, these factors may cause de-differentiation of the tumor cells leading to cancer stem cells that contribute to radio-, chemo- and immune-resistance and recurrence of tumors. On the other hand, they may also enhance the heterogeneity under specific microenvironment-driven proliferation. In this editorial, we intend to underline the importance of heterogeneity in cancer progress, its evaluation and its use in correlation with the tumor evolution in a specific patient as a field of research for achieving precise patient-tailored treatments and amelioration of diagnostic (monitoring) tools and prognostic capacity.

• Klíčová slova
• Evolvability of tumor, Human endogenous retroviruses, Metabolic heterogeneity, Tumor heterogeneity, Tumor metastasis heterogeneity,
• MeSH
• extracelulární matrix MeSH
• lidé MeSH
• nádorové kmenové buňky MeSH
• nádorové mikroprostředí genetika   MeSH
• nádory * genetika   MeSH
• patologická angiogeneze MeSH
• proliferace buněk genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• úvodníky MeSH

Cytokines and chemokines are important regulators of innate and specific responses in leishmaniasis, a disease that currently affects 12 million people. We overviewed the current information about influences of genetically engineered mouse models of cytokine and chemokine on leishmaniasis. We found that genetic background of the host, parasite species and sub-strain, as well as experimental design often modify effects of genetically engineered cytokine genes. Next we analyzed genes and QTLs (quantitative trait loci) that control response to Leishmania species in mouse in order to establish relationship between genetic control of cytokine expression and organ pathology. These studies revealed a network-like complexity of the combined effects of the multiple functionally diverse QTLs and their individual specificity. Genetic control of organ pathology and systemic immune response overlap only partially. Some QTLs control both organ pathology and systemic immune response, but the effects of genes and loci with the strongest impact on disease are cytokine-independent, whereas several loci modify cytokines levels in serum without influencing organ pathology. Understanding this genetic control might be important in development of vaccines designed to stimulate certain cytokine spectrum.

• Klíčová slova
• Chemokines, Cytokines, Genetic control, Integrative network, Leishmania,
• MeSH
• cytokiny genetika   MeSH
• interakce hostitele a parazita genetika   MeSH
• Leishmania patogenita   MeSH
• leishmanióza genetika   parazitologie   MeSH
• lidé MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cytokiny MeSH

BACKGROUND: Interleukin-35 (IL-35) is a recently described heterodimeric cytokine that belongs to the IL-12 family and consists of p35 (IL-12a) and EBI3 (IL-27b) subunits. The expression of IL-35 in humans is inducible in response to inflammatory stimuli. Increased IL-35 levels were documented in several autoimmune inflammatory diseases, suggesting a possible immunomodulatory role in their pathogenesis. OBJECTIVES: The aim of this study was to explore a potential role of IL-35 in the pathogenesis of idiopathic inflammatory myopathies (IIM) by studying the expression of IL-35 subunits in muscle biopsy samples and by evaluating serum levels of IL-35 and their association with disease activity in IIM patients. METHODS: The expression of IL-35 subunits was studied in serial sections of 9 muscle biopsy samples [4 polymyositis (PM), 5 dermatomyositis (DM)] and in 7 non-inflammatory control muscle biopsies. Serum levels of IL-35 were measured in 23 PM, 28 DM and 15 cancer associated myositis (CAM) patients as well as in 40 healthy controls. Disease activity was evaluated using the Myositis Disease Activity Assessment Tool (MDAAT) and by serum muscle enzymes. RESULTS: Expression of both IL-35 subunits was evident in the inflammatory infiltrates in IIM muscle biopsies, while no IL-35 expression was observed in control muscle samples. IL-35 serum levels were increased in all IIM patients compared to healthy controls [median 119.5 (range 32.1-1074.5) vs 36.2 (range 1.5-86.5) pg/ml, P < 0.001]. There were no differences in IL-35 serum levels between myositis subgroups (DM, PM or CAM). Serum IL-35 levels correlated significantly with physician's assessment of global (r = 0.29, p = 0.021), muscle (r = 0.30, p = 0.017) and extramuscular (r = 0.30, p = 0.016) disease activity as well as creatine kinase (r = 0.26, p = 0.044) and lactate dehydrogenase (r = 0.40, p = 0.003) levels. There was a significant correlation with pulmonary activity in patients with interstitial lung disease (r = 0.39, p = 0.037). Serum IL-35 correlated negatively with duration of treatment (r = -34, p = 0.009). CONCLUSIONS: IL-35 is overexpressed in inflammatory infiltrates in muscle tissue and serum in IIM patients and there is correlation with several disease activity parameters. These data suggest potential role of locally produced IL-35 in the pathogenesis of inflammatory myopathies.

• Klíčová slova
• Disease activity, IL-35, Idiopathic inflammatory myopathy, Muscle biopsy,
• MeSH
• biopsie MeSH
• dítě MeSH
• dospělí MeSH
• interleukiny krev   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myozitida krev   metabolismus   patologie   MeSH
• polymyozitida krev   metabolismus   patologie   MeSH
• senioři MeSH
• svaly metabolismus   patologie   MeSH
• upregulace MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interleukin-35, human MeSH Prohlížeč
• interleukiny MeSH

Supraphysiological levels of IL-7 induce increase counts of pre-B cells, naive T cells and memory phenotype CD8+ T cells. Immunocomplexes of IL-7 and αIL-7 mAb M25 (IL-7/M25) were described as IL-7 superagonist in vivo. Thus, treatment of mice with IL-7/M25 remarkably increases the size of the T cell pool. We decided to use IL-7/M25 in order to expand the T cell population prior to the administration of αCTLA-4 and αPD-1 mAbs in tumor-bearing mice and in turn boost the immunotherapy based on a combination of CTLA-4 and PD-1 blockage. We found that just four doses of IL-7/M25 increased the absolute numbers of splenocytes approximately fivefold and significantly shifted the CD4+:CD8+ T cell ratio in favor of CD8+ T cells. There was also a substantive increase in relative counts of memory phenotype CD8+ T cells (approximately threefold) within CD8+ T cells but a significant decrease (approximately 30%) in relative counts of Treg cells within CD4+ T cells. All these data suggest that IL-7/M25 offer a suitable approach to potentiate tumor immunotherapy through CTLA-4 and PD-1 blockage. Unexpectedly, IL-7/M25 significantly abrogated the antitumor activity of αCTLA-4 plus αPD-1 mAbs in the following mouse tumor models: MC-38 and CT26 colon carcinoma and B16F10 melanoma. This paradoxical effect of IL-7/M25 on the antitumor activity of CTLA-4 and PD-1 blockage was not mediated via either increased levels of IL-10 or TGF-β in the sera or increased counts of IL-10-producing B or T cells in the spleen of mice injected with IL-7/M25. Thus, our work shows that caution should be exercised when combining two immunotherapy approaches together.

• Klíčová slova
• Antitumor activity, CTLA-4, IL-7, IL-7 immunocomplexes, Immunotherapy, PD-1,
• MeSH
• antigen CTLA-4 imunologie   MeSH
• antigeny CD279 imunologie   MeSH
• antitumorózní látky imunologie   MeSH
• CD4-pozitivní T-lymfocyty imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• imunoterapie metody   MeSH
• interleukin-10 imunologie   MeSH
• interleukin-7 imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom imunologie   MeSH
• modely nemocí na zvířatech MeSH
• monoklonální protilátky imunologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory tračníku imunologie   MeSH
• regulační T-lymfocyty imunologie   MeSH
• transformující růstový faktor beta imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• antigeny CD279 MeSH
• antitumorózní látky MeSH
• CTLA4 protein, human MeSH Prohlížeč
• IL7 protein, human MeSH Prohlížeč
• interleukin-10 MeSH
• interleukin-7 MeSH
• monoklonální protilátky MeSH
• PDCD1 protein, human MeSH Prohlížeč
• transformující růstový faktor beta MeSH

Interleukin-1α (IL-1α) and Annexin A2 (AnxA2) are pleiotropic molecules with both intracellular and extracellular roles. They share several characteristics including unconventional secretion aided by S100 proteins, anchoring of the externalized proteins at the outer surface of the plasma membrane and response to oxidative stress. Although IL-1α and AnxA2 have been implicated in a variety of biological processes, including cancer, little is known about the mechanisms of their cellular release. In the present study, employing the non-cancerous breast epithelial MCF10A cells, we demonstrate that IL-1α and AnxA2 establish a close association in response to oxidative stress. Stress conditions lead to translocation of both proteins towards lamellipodia rich in vimentin and association of full-length IL-1α and Tyr23 phosphorylated AnxA2 with the plasma membrane at peripheral sites depleted of F-actin. Notably, membrane-associated IL-1α and AnxA2 preferentially localize to the outer edges of the MCF10A cell islands, suggesting that the two proteins participate in the communication of these epithelial cells with their neighboring cells. Similarly, in U2OS osteosarcoma cell line both endogenous IL-1α and transiently produced IL-1α/EGFP associate with the plasma membrane. While benign MFC10A cells present membrane-associated IL-1α and AnxA2 at the edges of their cell islands, the aggressive cancerous U2OS cells communicate in such manner also with distant cells.

• Klíčová slova
• Annexin A2, Interleukin-1α, MCF10A, Oxidative stress, Unconventional secretion,
• MeSH
• aktiny metabolismus   MeSH
• annexin A2 metabolismus   MeSH
• buněčná membrána metabolismus   MeSH
• epitelové buňky metabolismus   MeSH
• fosforylace fyziologie   MeSH
• interleukin-1alfa metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• oxidační stres fyziologie   MeSH
• proteiny S100 metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aktiny MeSH
• annexin A2 MeSH
• ANXA2 protein, human MeSH Prohlížeč
• IL1A protein, human MeSH Prohlížeč
• interleukin-1alfa MeSH
• proteiny S100 MeSH

BACKGROUND: Acute myeloid leukemia (AML) cells are highly resistant to chemotherapeutic drugs. Cytokines and adhesion molecules may contribute to this resistance and affect treatment outcome. The aim of this study was to evaluate the independence and additional prognostic information of baseline serum levels of selected cytokines and soluble adhesion molecules, included in analyses with standard prognostic indicators. METHODS: We used biochip array technology to measure levels of selected cytokines and soluble adhesion molecules in serum samples of 80 newly diagnosed AML patients. The markers of tumour microenvironment were analysed against high risk karyotype, hyperleucocytosis, higher age, lactic dehydrogenase levels and presence of FLT3-ITD and NPM-1 mutation. RESULTS: All evaluated analytes were independent of standard prognostic indicators. Fifteen were associated with overall and eight with progression-free survival in univariate analysis. After correction for multiple testing, we identified soluble interleukin-2 receptor-α as an independent indicator of overall survival. Further, the soluble type I TNF-α receptor was close to statistical significance for both overall and progression-free survival. CONCLUSIONS: Baseline levels of soluble interleukin-2 receptor-α predict overall survival in newly diagnosed AML. The TNF-α type I soluble receptor is a candidate prognostic marker in AML and is worth of further investigation.

• Klíčová slova
• Acute myeloid leukemia, Adhesion molecules, Cytokines, Prognosis, sIL-2Rα,
• MeSH
• akutní myeloidní leukemie krev   genetika   mortalita   MeSH
• cytokiny krev   MeSH
• doba přežití bez progrese choroby MeSH
• interleukin-2 krev   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• molekuly buněčné adheze krev   MeSH
• mutace genetika   MeSH
• nádorové mikroprostředí fyziologie   MeSH
• prognóza MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• IL2 protein, human MeSH Prohlížeč
• interleukin-2 MeSH
• molekuly buněčné adheze MeSH

OBJECTIVES: Little is known about the role of adipokines in the pathogenesis of coronary artery disease in young patients. The aims of this study were to compare serum levels of adipokines and expression of adipokines in peripheral blood leukocytes in patients with premature coronary artery disease (CAD), metabolic syndrome and healthy individuals. DESIGN AND METHODS: Sixty-five patients with premature CAD (men 18-45years old and women 18-55years old) formed the study group. The control groups were 75 patients with metabolic syndrome and 50 healthy individuals. For each group, RNA expression in peripheral blood leukocytes was determined for 24 different adipokines and 11 adipokines were examined in serum. RESULTS: In individuals with CAD, serum visfatin levels were significantly higher than in metabolic syndrome and healthy controls (2.3 vs. 1.6 vs. 0.7µg/L, P<0.001) while both omentin-1 (92.9 vs. 587.0 vs. 552.3µg/L, P<0.001) and ZAG2 (45.5 vs. 72.5 vs. 77.1mg/L, P<0.001) levels were lower. The receiver operating curve (ROC) analysis for testing the validity of these adipokines in the diagnosis of CAD compared to control groups provided the following areas under the curve (AUC): omentin-1 AUC 0.97 (cut-off ≤222µg/L), ZAG2 AUC 0.89 (cut-off ≤51.7mg/L) and visfatin AUC 0.74 (cut-off ≥1.0µg/L) (P<0.001 in all cases). Visfatin and omentin-1 serum levels did not differ between the acute phase of myocardial infarction and the chronic phase of CAD. In patients with CAD, we found no significant relation between mRNA expression and adipokine concentration. CONCLUSION: Serum omentin-1, visfatin and ZAG2 could serve as biomarkers of premature CAD in young apparently healthy people.

• Klíčová slova
• Acute myocardial infarction, Adipokine expression, Adipokines, Metabolic syndrome, Premature coronary artery disease, Young adults,
• MeSH
• adipokiny krev   genetika   metabolismus   MeSH
• cytokiny krev   genetika   MeSH
• dospělí MeSH
• GPI-vázané proteiny krev   genetika   MeSH
• infarkt myokardu krev   genetika   MeSH
• kohortové studie MeSH
• lektiny krev   genetika   MeSH
• leukocyty metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA krev   MeSH
• metabolický syndrom krev   genetika   MeSH
• mladiství MeSH
• nemoci koronárních tepen krev   genetika   MeSH
• nikotinamidfosforibosyltransferasa krev   genetika   MeSH
• podkožní tuk metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adipokiny MeSH
• AZGP1 protein, human MeSH Prohlížeč
• cytokiny MeSH
• GPI-vázané proteiny MeSH
• ITLN1 protein, human MeSH Prohlížeč
• lektiny MeSH
• messenger RNA MeSH
• nicotinamide phosphoribosyltransferase, human MeSH Prohlížeč
• nikotinamidfosforibosyltransferasa MeSH

BACKGROUND: S100A11 (calgizzarin), a member of the S100 family, is associated with oncogenesis, inflammation and myocardial damage. Our aim was to analyse S100A11 in idiopathic inflammatory myopathies (IIMs) and its association with disease activity features and cancer development. METHODS: S100A11 in muscle was determined by immunohistochemistry in polymyositis (PM), dermatomyositis (DM), myasthenia gravis (MG) and in subjects without autoimmune inflammatory disease (HC). S100A11 in plasma was measured in 110 patients with IIMs (PM, DM, and cancer associated myositis (CAM) patients) and in 42 HC. Disease activity was assessed by myositis disease activity assessment (MYOACT), muscle enzymes and C-reactive protein (CRP) were measured by routine laboratory techniques; autoantibodies by immunoprecipitation or by immunoblot. RESULTS: We observed an accumulation of S100A11 in the cytoplasm of regenerating and necrotizing muscle fibres of PM and DM patients. S100A11 was increased in plasma of all myositis patients compared to HC (3.8 (1.5-16.8) vs 2.8 (1.7-11.2) ng/ml, p = 0.011) and in DM and CAM patients compared to HC (4.0 (2.2-14.9) and 4.5 (1.5-9.1) vs 2.8 (1.7-11.2) ng/ml, p < 0.001 and p = 0.022, respectively). In all myositis patients, S100A11 correlated with the levels of lactate dehydrogenase (r = 0.256, p = 0.011), aspartate aminotransferase (AST) (r = 0.312, p = 0.002), CRP (r = 0.254, p = 0.022) and MYOACT (r = 0.245, p = 0.022). S100A11 was associated with MYOACT (r = 0.377, p = 0.030) and pulmonary and cutaneous disease activity in DM patients (r = 0.408, p = 0.017 and r = 0.417, p = 0.01, respectively). S100A11 was related to the levels of AST (r = 0.412, p = 0.027) in PM and to the levels of creatine phosphokinase (r = 0.432, p = 0.028) in CAM patients. CONCLUSIONS: We show for a first time a potential implication of S100A11 in the local inflammatory and tissue remodelling processes in myositis and an association of circulating S100A11 with disease activity and extra muscular manifestations in DM.

• Klíčová slova
• Calgizzarin, Disease activity, Inflammation, Myositis, S100 proteins,
• MeSH
• autoimunitní nemoci imunologie   patologie   MeSH
• autoprotilátky imunologie   MeSH
• C-reaktivní protein analýza   MeSH
• dospělí MeSH
• kosterní svalová vlákna patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• polymyozitida imunologie   patologie   MeSH
• proteiny S100 metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• autoprotilátky MeSH
• C-reaktivní protein MeSH
• proteiny S100 MeSH
• S100A11 protein, human MeSH Prohlížeč

BACKGROUND: Interleukin (IL)-20 is a pro-inflammatory cytokine that may be implicated in the pathogenesis of rheumatoid arthritis (RA). This study aimed to determine the association between IL-20 and disease activity in patients with RA. METHODS: The levels of serum and synovial fluid IL-20 were measured in patients with RA and OA. The disease activity was assessed based on the Disease Activity Score of 28 joints (DAS28). The expression of IL-20 in synovial tissue samples from patients with RA and OA were determined by immunohistochemistry. Immunofluorescence staining was used to co-localize IL-20 with selected cells. The secretion of IL-20 was analysed in human peripheral blood mononuclear cells (PBMCs) of patients with RA. RESULTS: Synovial fluid and synovial tissue IL-20 were significantly increased in patients with RA compared with patients with OA. The expression of IL-20 in RA synovial tissue was particularly associated with macrophages and neutrophil granulocytes, but also with synovial fibroblasts and lymphocytes. The IL-20 levels in synovial fluid correlated with DAS28 (r=0.434; p=0.015) and were significantly elevated in anti-CCP positive RA compared with anti-CCP negative RA (122.3±104.1pg/ml and 45.9±35.8pg/ml; p=0.008). IL-20 production from PBMCs was induced by Poly I:C and LPS but not with pro-inflammatory cytokines, such as TNF-α or IL-1. CONCLUSION: Our data showed that IL-20 is independently associated with RA disease activity and may be triggered by TLR ligands at local sites of inflammation.

• Klíčová slova
• Disease activity, Inflammation, Interleukin-20, Rheumatoid arthritis,
• MeSH
• dospělí MeSH
• imunohistochemie MeSH
• interleukiny krev   metabolismus   MeSH
• leukocyty mononukleární účinky léků   imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• ligandy MeSH
• lipopolysacharidy imunologie   MeSH
• revmatoidní artritida krev   imunologie   patofyziologie   MeSH
• senioři MeSH
• synoviální tekutina imunologie   MeSH
• toll-like receptory imunologie   MeSH
• zánět MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• interleukin 20 MeSH Prohlížeč
• interleukiny MeSH
• ligandy MeSH
• lipopolysacharidy MeSH
• toll-like receptory MeSH