scholarly journals ET-11 ANALYSIS OF ANTI-GLIOMA EFFECT BY PROINFLAMMATORY CYTOKINES

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii9-ii9
Author(s):  
Koji Adachi ◽  
Fumio Yamaguchi ◽  
Tadashi Higuchi ◽  
Hirosi Takahashi ◽  
Akio Morita
Keyword(s):  
Proinflammatory Cytokines ◽  
Mononuclear Cells ◽  
Cytokine Receptors ◽  
Tnf Alpha ◽  
Ifn Gamma ◽  
Subcutaneous Transplantation ◽  
Cell Cycle Alteration ◽  
Antiglioma Activity ◽  
Anti Tumor Activity ◽  
Transplantation Model

Abstract OBJECT Antiglioma activity of proinflammatory cytokines, (TNF-alpha, IL-2, IL-12 related cytokines, IL-18, IL-32) are analyzed. Most effective combinations of cytokines are investigated. MATERIAL & METHOD Antitumor activity against U373MG, U87MG were measured by co-culture with PBMC and by nude mouse subcutaneous transplantation model. Cytokine receptors on PBMC and glioma cell lines were examined by IHC and mRNA expression. Anti-tumor activity was measured by local injection and systemic administration of proinflammatory cytokines. Cell cycle alteration and expression of apoptosis-related genes after cytokine administration was analyzed. Serum concentraion of cytokines is measured by ELISA. RESULT Cytokine receptors were not expressed on glioma cells but were present on intratmoral mononuclear cells. Anti-tumor activity against transplanted tumor is strongly observed by focal administration. Expression of apoptosis-related genes were augmented. IFN-gamma was strongly induced by TNF-alpha, IL-2 and IL-12 administration. IFN-gamma, IL-17, TNF-alpha were also induced. IL-27 and IL-32 per se did not induce IFN-gamma. Simultaneous IL-27 and IL-12 induced strong IFN-gamma induction. Anti-glioma activity of IL-12 and IL-23 were higher than the same dose of exogenous IFN-gamma. IFN-gamma, IL-2 plus IL-12 in U373MG, and IFN-gamma, IL-2 plus IL-18 in U87MG seemed to be the best combination. CONCLUSIONS Strong anti-glioma activity was induced by proinflammatory cytokines at least partially through IFN-gamma. There may be another factors. IL-2 and IL-23 showed anti-tumor activity through IFN-gamma, IL-17, TNF-alpha. IFN-gamma + IL-2 + IL-12/-18 seems to be the best combination.

scholarly journals Inhibition of CD4 cross-linking-induced lymphocytes apoptosis by vesnarinone as a novel immunomodulating agent: vesnarinone inhibits Fas expression and apoptosis by blocking cytokine secretion

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2361-2368 ◽  
Author(s):  
N Oyaizu ◽  
TW McCloskey ◽  
S Than ◽  
S Pahwa
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Cytokine Secretion ◽  
Tnf Alpha ◽  
Cross Linking ◽  
Apoptosis Induction ◽  
Peripheral Blood Mononuclear ◽  
Cell Surface Molecule ◽  
Ifn Gamma

Evidence is accumulating that T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals show accelerated cell death through apoptosis. We have recently demonstrated that the cross-linking of CD4 molecules (CD4XL) results in death of normal peripheral T cells through apoptosis and imbalanced cytokine secretion (ie, induction of tumor necrosis factor-alpha [TNF-alpha] and interferon-gamma [IFN-gamma] in the absence of interleukin-2 [IL-2] or IL-4 secretion). These upregulated cytokines (TNF-alpha/IFN-gamma) largely contributed to upregulation of the apoptosis-inducing cell surface molecule, Fas (APO- 1/CD95) and apoptosis induction. The present study investigated the effect of vesnarinone as a novel immunomodulating agent on CD4XL- induced T-cell apoptosis. The addition of vesnarinone to peripheral blood mononuclear cells (PBMC) significantly inhibited CD4XL-induced lymphocyte apoptosis. This apoptosis-inhibitory effect of vesnarinone was associated with the blocking of CD4XL-induced TNF-alpha IFN-gamma secretion and of Fas antigen upregulation. However, vesnarinone did not block effects of exogenously supplemented TNF-alpha/IFN-gamma on Fas induction. These data suggest that vesnarinone inhibits CD4XL-induced TNF-alpha/IFN-gamma secretion, thereby blocking subsequent Fas upregulation and apoptosis induction. Given the potent pathogenic role of imbalanced cytokine secretion observed in HIV-infection, an agent such as vesnarinone may be of therapeutic value in slowing disease progression.

scholarly journals Lymphokine overproduction in severe aplastic anemia is not related to blood transfusions

Blood ◽  
1989 ◽  
Vol 74 (8) ◽  
pp. 2713-2717 ◽  
Author(s):  
W Hinterberger ◽  
G Adolf ◽  
P Bettelheim ◽  
K Geissler ◽  
C Huber ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Aplastic Anemia ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Severe Aplastic Anemia ◽  
Tnf Alpha ◽  
Blood Transfusions ◽  
Peripheral Blood Mononuclear ◽  
Ifn Gamma

Abstract The production of interferons (IFNs), IFN-gamma, tumor necrosis factors (TNFs) and TNF-alpha (TNF-alpha) by peripheral blood mononuclear cells (PBMNCs) of untransfused and transfused, but otherwise untreated patients with severe aplastic anemia (SAA) was determined using bioassays and immunoassays. In untransfused and pretransfused SAA patients, spontaneous and lectin-induced production of these cytokines by PBMNCs was strongly enhanced. Cytokine production in untransfused SAA patients did not differ from that in pretransfused patients. Similar relative frequencies of activated (HLA-DR+) lymphocyte subpopulations present in the PBMNCs demonstrated cytokine overproduction per cells. Cytokine production was studied in three SAA patients before and after blood cell transfusions. Spontaneous and lectin-induced production of these cytokines was abnormally high and unaffected by blood transfusions. In another patient exhibiting abnormal cytokine production, the hematopoietic response to cyclosporin- A in vivo was accompanied by normalization of cytokine production in vitro. We conclude that overproduction of IFN-gamma and TNF-alpha by lectin-stimulated PBMNCs is an intrinsic abnormality of SAA unrelated to blood transfusions. Normalization of production of IFN-gamma and TNF- alpha accompanying a clinical response to cyclosporin-A may cautiously be taken as further evidence suggesting a pathogenetic role of cytokine overproduction in SAA.

Volatile Anesthetics Augment Expression of Proinflammatory Cytokines in Rat Alveolar Macrophages during Mechanical Ventilation 

1999 ◽  
Vol 91 (1) ◽  
pp. 187-197 ◽  
Author(s):  
Naoki Kotani ◽  
Satoshi Takahashi ◽  
Daniel I. Sessler ◽  
Eiji Hashiba ◽  
Takeshi Kubota ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mechanical Ventilation ◽  
Proinflammatory Cytokines ◽  
Alveolar Macrophages ◽  
Surgical Stress ◽  
Internal Standard ◽  
Volatile Anesthetics ◽  
Tnf Alpha ◽  
Transcriptional Level ◽  
Ifn Gamma

Background Previous studies indicate that anesthesia and surgery induce an inflammatory reaction in alveolar macro phages. However,they filed to independently evaluate the relative contributions of factors including mechanical ventilation, general anesthesia, and surgical stress. Therefore, the authors tested the hypothesis that inflammatory reactions at the cellular level in alveolar macrophages are induced within 2 h of inhalation of volatile anesthetics under mechanical ventilation. Methods After administration of pentobarbital, rats were allocated to the nonventilated control or spontaneous or mechanical ventilation (n = 15/group) for 2 h at a fraction of inspired oxygen (FI(O2)) of 0.21. In a separate series of experiments, rats were mechanically ventilated without volatile anesthesia, or during exposure to halothane, enflurane, isoflurane, or sevoflurane (n = 15/group). Pulmonary lavage was performed, and RNA was extracted from harvested cells. The mRNA for the proinflammatory cytokines interleukin (IL)-1alpha, IL-1beta, IL-6, macrophage inflammatory protein-2 (MIP-2), interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) were measured by semiquantitative reverse transcription-polymerase chain reaction using beta-actin as an internal standard. Pulmonary lavage concentrations of these cytokines were measured by enzyme-linked immunoassay. Results The lavage cell count and cytology were similar in each series of the experiment. Gene expression of MIP-2 and TNF-alpha was greater during mechanical than spontaneous ventilation and nonventilation control However, the concentrations of cytokines except MIP-2 and TNF-alpha were less than detection levels. During exposure to volatile anesthetics, gene expression for IL-1beta, MIP-2, IFN-gamma, and TNF-alpha all increased significantly compared with mechanical ventilation alone. Significant increases in lavage concentrations of MIP-2 and TNF-alpha were also observed. Conclusions Gene expression of proinflammatory cytokines increase after inhalation of volatile anesthetics under mechanical ventilation. These data indicate that inhalation of volatile anesthetics under mechanical ventilation induces an inflammatory response at the transcriptional level within 2 h.

Cytokine expression in dogs with naturalLeishmania infantuminfection

Parasitology ◽  
2009 ◽  
Vol 136 (8) ◽  
pp. 823-831 ◽  
Author(s):  
M. A. PANARO ◽  
O. BRANDONISIO ◽  
A. CIANCIULLI ◽  
P. CAVALLO ◽  
V. LACASELLA ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Clinical Status ◽  
Clinical Signs ◽  
Cytokine Expression ◽  
Tnf Alpha ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Ifn Gamma ◽  
First Diagnosis

SUMMARYThe aim of this study was to evaluate cytokine expression in 22Leishmania infantumnaturally infected dogs, in order to correlate this parameter with the clinical status of infected animals. After 4 and 8 months from the first diagnosis ofLeishmaniainfection, clinical and laboratory examination of dogs was performed and peripheral blood mononuclear cells (PBMC) were isolated. The cytokine profile was analysed in terms of IFN-gamma, IL-4, IL-10 and TNF-alpha mRNA expression in cultured PBMC by a semi-quantitative reverse transcriptase-PCR. Thirteen out of 22Leishmania-infected dogs remained asymptomatic in the follow-up, while 9 showed clinical signs of leishmaniasis. IL-4, IL-10, TNF-alpha and IFN-gamma mRNA levels were not significantly different in asymptomatic compared to symptomatic animals 4 months from the diagnosis ofLeishmaniainfection, but were significantly higher in symptomaticversusasymptomatic dogs after 8 months from diagnosis. In addition, IL-4, IL-10 and TNF-alpha mRNA levels significantly increased only in symptomatic dogs at 8 months, in comparison to the levels found at 4 months. These results show a mixed Th1 and Th2 cytokine response inLeishmania-infected dogs, with higher cytokine expression in dogs with manifest clinical disease, during the second follow-up after 8 months from the first diagnosis of infection.

scholarly journals Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1458-1465 ◽  
Author(s):  
RK Gherardi ◽  
L Belec ◽  
M Soubrier ◽  
D Malapert ◽  
M Zuber ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proinflammatory Cytokines ◽  
Transforming Growth Factor Beta ◽  
Proinflammatory Cytokine ◽  
Transforming Growth Factor ◽  
Serum Levels ◽  
Poems Syndrome ◽  
Tnf Alpha ◽  
Tgf Beta ◽  
Ifn Gamma

The polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome is a rare multisystem disorder of obscure pathogenesis associated with osteosclerotic myeloma. Circulating levels of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-alpha) interleukin-1 beta [IL-1 beta], IL-2, IL-6, and interferon-gamma [IFN- gamma]), anti-inflammatory cytokines (transforming growth factor beta 1 [TGF beta 1], IL-4, IL-10, and IL-13), the cytokine carrier protein alpha 2 macroglobulin, IL-1 receptor antagonist (IL-1ra), soluble TNF receptors (sTNFr) p55 and p75, and soluble IL-6 receptor (sIL-6r) were determined in 15 patients with POEMS syndrome and 15 with multiple myeloma. Patients with POEMS syndrome had higher serum levels of IL-1 beta, TNF-alpha, and IL-6 and lower serum levels of TGF beta 1 than did patients with multiple myeloma. Serum levels of IL-2, IL-4, IL-10, IL- 13, IFN-gamma, alpha 2 macroglobulin, and sIL-6r were similar in both groups. IL-1ra and sTNFrs were increased in POEMS syndrome, but out of proportion to the increase of IL-1 beta and TNF-alpha. Serial evaluations in 1 patient showed that proinflammatory cytokine serum levels paralleled disease activity assessed by platelet count and neurologic involvement. Our results suggest that the manifestations of POEMS syndrome might be regarded as the result of a marked activation of the proinflammatory cytokine network (IL-1 beta, IL-6, and TNF- alpha) associated with a weak or even decreased (TGF beta 1) antagonistic reaction insufficient to counteract the noxious effects of cytokines.

scholarly journals Adherent lymphokine-activated killer cells suppress autologous human normal bone marrow progenitors

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2389-2395 ◽  
Author(s):  
JS Miller ◽  
C Verfaillie ◽  
P McGlave
Keyword(s):  
Bone Marrow ◽  
Neutralizing Antibodies ◽  
Mononuclear Cells ◽  
Colony Growth ◽  
Suppressive Effect ◽  
Lak Cells ◽  
Tnf Alpha ◽  
Lymphokine Activated Killer Cells ◽  
Ifn Gamma ◽  
Dose Dependent

Abstract We have generated a homogeneous population of recombinant interleukin-2 (rIL-2)-stimulated effector cells termed adherent lymphokine-activated killer cells (A-LAK) from peripheral blood mononuclear cells (PBMNC) of 14 normal individuals and tested the effect of A-LAK cells on autologous hematopoietic bone marrow (BM) progenitor growth. Enrichment of A-LAK from PBMNC depended on the propensity of A-LAK precursors to adhere to plastic and proliferate in the presence of rIL-2. The resultant population had the morphologic appearance of large granular lymphocytes, and the majority of cells (73% +/- 4%) expressed the CD56+/CD3- phenotype associated with rIL-2-stimulated natural killer (NK) cells. The A-LAK population had potent lytic activity in chromium release assays against both NK-sensitive (K562) and NK-resistant (Raji) targets. When BM mononuclear cells (BMMNC) were coincubated with autologous A-LAK and rIL-2 (1,000 U/mL) added at the start of culture, dose-dependent suppression of burst-forming unit-erythroid (BFU-E) and colony-forming unit mix (CFU-MIX) colony growth was observed at effector to target ratios (E:T) ranging from 0.25:1 to 5:1 (maximal suppression BFU-E = 85% +/- 6%; CFU-MIX = 95% +/- 3%). This suppression was rIL-2 dose-dependent, and no suppression was seen in the absence of rIL-2. Depletion of BM monocytes and T lymphocytes did not alter A-LAK suppression of progenitors coincubated with A-LAK cells. Addition of polyclonal neutralizing antibodies against both interferon-gamma (IFN- gamma) and tumor necrosis facto alpha (TNF-alpha) to the coincubation culture completely abrogated the suppressive effect of A-LAK on BFU-E and CFU-MIX colony growth while each neutralizing antibody used alone had intermediate effects. In contrast to coincubation studies, 36 hours of preincubation of A-LAK cells with autologous BM (E:T 2.2:1) and rIL- 2 (1,000 U/mL) followed by plating of preincubated BM cells in hematopoietic progenitor culture produced significant suppression of day 14 BFU-E (47% +/- 5%), but spared the more primitive CFU-MIX (7% +/- 9%), suggesting a divergent effect of A-LAK cells on hematopoietic progenitors at different stages of differentiation. Addition of neutralizing antibodies against IFN-gamma and TNF-alpha in preincubation failed to abrogate the suppressive effect of A-LAK on BFU- E colony growth, suggesting that this suppression occurs by a different mechanism than that seen in coincubation studies. Previous studies have demonstrated that the A-LAK population has cytotoxic and proliferative advantages over other killer cell populations.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Downregulation of proinflammatory cytokine release in whole blood from septic patients

Blood ◽  
1995 ◽  
Vol 85 (5) ◽  
pp. 1341-1347 ◽  
Author(s):  
W Ertel ◽  
JP Kremer ◽  
J Kenney ◽  
U Steckholzer ◽  
D Jarrar ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Mrna Expression ◽  
Proinflammatory Cytokines ◽  
Whole Blood ◽  
Mononuclear Cells ◽  
Natural Infection ◽  
Tnf Alpha ◽  
Control Group ◽  
Cytokine Release ◽  
Septic Group

Using animal models or healthy volunteers, injection of lipopolysaccharide (LPS) or bacteria causes activation of macrophages with excessive synthesis and secretion of proinflammatory cytokines. Although these models mimic the effects of LPS in the host, they may represent more of an experimental expression of endotoxemia than natural infection itself. Therefore, as an ex vivo model of sepsis, whole blood from 15 patients with severe sepsis and 20 control patients without infection was stimulated with LPS to study the kinetics of mRNA expression and release of proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and IL-6. Stimulation of whole blood with 1 microgram/mL LPS resulted in a maximum increase of cytokine secretion in the control group, while a marked (P < .01) depression of TNF-alpha, IL-1 beta, and IL-6 release was observed in the septic group, which persisted up to 10 days after study enrollment. While IL-1 beta mRNA expression was similar in peripheral blood mononuclear cells (PBMCs) harvested from LPS-stimulated whole blood in septic and control patients, the half-life and consequently the expression of TNF-alpha and IL-6 mRNA were strongly reduced in the septic group. These data indicate a downregulatory mechanism of cytokine release in whole blood from patients with severe sepsis that occurs on different levels. Although excessive secretion of proinflammatory cytokines has been considered deleterious for the host, the reduced capacity of PBMCs in whole blood from septic patients to synthesize and secrete proinflammatory cytokines to an inflammatory stimulus may result in immunodeficiency, because these cytokines in low concentrations are involved in the upregulation of essential cellular and humoral immune functions.

scholarly journals Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone.

1996 ◽  
Vol 183 (3) ◽  
pp. 927-936 ◽  
Author(s):  
M Bianchi ◽  
O Bloom ◽  
T Raabe ◽  
P S Cohen ◽  
J Chesney ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Transforming Growth Factor Beta ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Tissue Injury ◽  
Human Peripheral Blood ◽  
No Production ◽  
Peripheral Blood Mononuclear ◽  
Ifn Gamma ◽  
Constitutive Synthesis

An overproduction of proinflammatory cytokines by activated macrophages/monocytes mediates the injurious sequelae of inflammation, septic shock, tissue injury, and cachexia. We recently synthesized a tetravalent guanylhydrazone compound (CNI-1493) that inhibits cytokine-inducible arginine transport and nitric oxide (NO) production in macrophages, and protects mice against lethal endotoxemia and carrageenan-induced inflammation. During these investigations we noticed that CNI-1493 effectively prevented lipopolysaccharide (LPS)-induced NO production, even when added in concentrations 10-fold less than required to competitively inhibit L-arginine uptake, suggesting that the suppressive effects of this guanylhydrazone compound might extend to other LPS-induced responses. Here, we report that CNI-1493 suppressed the LPS-stimulated production of proinflammatory cytokines (tumor necrosis factor [TNF], interleukins 1beta and 6, macrophage inflammatory proteins 1alpha and 1beta) from human peripheral blood mononuclear cells. Cytokine suppression was specific, in that CNI-1493 did not inhibit either the constitutive synthesis of transforming growth factor beta or the upregulation of major histocompatibility complex class II by interferon gamma (IFN-gamma). In contrast to the macrophage suppressive actions of dexamethasone, which are overridden in the presence of IFN-gamma, CNI-1493 retained its suppressive effects even in the presence of IFN-gamma. The mechanism of cytokine-suppressive action by CNI-1493 was independent of extracellular L-arginine content and NO production and is not restricted to induction by LPS. As a selective inhibitor of macrophage activation that prevents TNF production, this tetravalent guanylhydrazone could be useful in the development of cytokine-suppressive agents for the treatment of diseases mediated by overproduction of cytokines.

scholarly journals Proinflammatory cytokines inhibit the expression and function of human type I 5'-deiodinase in HepG2 hepatocarcinoma cells

2002 ◽  
pp. 559-566 ◽  
Author(s):  
TC Jakobs ◽  
B Mentrup ◽  
C Schmutzler ◽  
I Dreher ◽  
J Kohrle
Keyword(s):  
Enzyme Activity ◽  
Proinflammatory Cytokines ◽  
Promoter Activity ◽  
Tnf Alpha ◽  
Type I ◽  
Reverse T3 ◽  
Necrosis Factor Alpha ◽  
Iodothyronine Deiodinase ◽  
Ifn Gamma ◽  
Human Type

OBJECTIVE: The sick euthyroid syndrome in critically ill patients without primary disease of the thyroid gland is characterised by low serum total triiodothyronine (T3), normal to elevated thyroxine (T4), elevated reverse T3 (rT3) and normal TSH levels. The aim of this work was to clarify if impaired T4 and rT3 5'-deiodination is an underlying mechanism. DESIGN AND METHODS: We analysed the effect of the human recombinant proinflammatory cytokines interleukin (IL)-6 and IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on human type I 5'-iodothyronine deiodinase (5'DI) enzyme activity in the human hepatocarcinoma cell line HepG2, i.e. in a homologous human system. Furthermore, we analysed transcriptional effects of the cytokines by transient transfection assays using the luciferase or chloramphenicol acetyltransferase (CAT) reporter genes under the control of 1480 nucleotides of the human 5'DI promoter. RESULTS: IL-6 at 500 pg/ml and TNF-alpha at 25 ng/ml had no significant effect, whereas 100 ng/ml IFN-gamma or 10 ng/ml IL-1beta reduced 5'DI enzyme activity to 77.9 and 59.5% of control values. IFN-gamma did not alter, IL-6 and TNF-alpha moderately decreased (in the case of IL-6 only in the CAT system), and IL-1beta (0.01-10 ng/ml) dose-dependently inhibited 5'DI promoter activity to a minimum of 38.1%. CONCLUSION: IL-1beta inhibited both 5'DI enzyme and promoter activity and, thus, may exert its effect on thyroid hormone metabolism at least partially through direct inhibition of hepatic 5'DI gene transcription.

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