Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:BIOD00082 (IL-2)
 29,198 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of IL-10 on the generation of alloreactivity in primary mixed lymphocyte cultures (MLCs) were investigated. IL-10 inhibited in a dose-dependent fashion the alloantigen-induced proliferative responses. The suppressive effect was maximal when IL-10 was added at the beginning of the cultures, suggesting that it acts on the early stages of T cell activation. The proliferative responses were enhanced in the presence of a neutralizing anti-IL-10 mAb, indicating that endogenously produced IL-10 suppresses proliferation in primary MLC. The inhibitory effects of IL-10 were observed irrespective of whether irradiated allogeneic peripheral blood mononuclear cells, purified monocytes or freshly isolated B cells were used as stimulator cells. The proliferation of both the CD4+ and CD8+ T cell subsets was inhibited to a similar extent. The reduced proliferative responses were only minimally restored by high concentrations of exogenous IL-2, indicating that the effects of IL-10 are not exclusively due to inhibition of IL-2 synthesis. Furthermore, the production of IL-2, interferon (IFN)-gamma, IL-6, granulocyte macrophage colony stimulating factor, and tumor necrosis factor-alpha in primary MLCs was diminished by IL-10 and enhanced in the presence of anti-IL-10 mAb. The strongest effects were observed on the production of IFN-gamma. Although IL-10 reduces the proliferative responses, the ratios of CD3+CD4+ and CD3+CD8+ T cells remained the same in IL-10 treated and control cultures, yet the percentages of activated CD3+ T cells, as judged by CD25 and HLA-DR expression, were consistently reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin 10 inhibits allogeneic proliferative and cytotoxic T cell responses generated in primary mixed lymphocyte cultures. 128 62

The effects of Staphylococcus aureus enterotoxin A (SEA) and lipopolysaccharide (LPS) in cytokine production were assessed at the single cell level in cells obtained from healthy blood donors. Cytokine production was studied with UV-microscopy of fixed and permeabilized cells stained with cytokine specific monoclonal antibodies. The cytokines evaluated included tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha, IL-1 beta, IL-6, IL-8, IL-10, IL-2, IL-4, interferon (IFN)-gamma and TNF-beta. LPS exhibited marked production of IL-1 alpha, IL-1 beta, TNF-alpha, IL-6 and IL-8. After LPS stimulation IL-1 alpha, IL-1 beta, TNF-alpha and IL-8 were the dominating products, all peaking at or before 4 hours after cell stimulation. In addition, IL-10 production was evident after 12 hours of cell stimulation. The T-lymphocyte-derived cytokines TNF-beta, IL-2, IFN-gamma and IL-4 were never detected in the cultures. All cytokine production, except IL-8, was downregulated at 96 hours. In contrast, peak production of IL-1 alpha, IL-1 beta and IL-8, which were the dominant products, occurred after 12 hours in the SEA-stimulated cultures. Further, a significant T-lymphocyte production of TNF-beta, TNF-alpha, IFN-gamma and IL-2 was found with peak production 12-48 hours after initiation. Only low amounts of IL-6 were evident. The two types of cytokine pattern and kinetics found may correspond to the different clinical conditions after invasive Gram-negative Escherichia coli vs Gram-positive Staphylococcus aureus infections in humans, with a much more rapid onset of disease after E. coli infections.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endotoxin and Staphylococcus aureus enterotoxin A induce different patterns of cytokines. 129 33

Rheumatoid arthritis (RA) is an immune disease in which the pathological immune reaction is thought to be initiated by the presentation of an (auto) antigen or superantigen by MHC class II positive cells to CD4 T cells. These successive immunological events can be studied by the cytokines produced at the different stages. Cytokine secretion by stimulated cells in autologous diluted whole blood has allowed the study of the immune profile characteristic of rheumatoid arthritis. The pattern of RA patient whole blood cells cultured in autologous blood is characterized by hyperactivity of the mononuclear cells with high secretion of IL-1 beta, TNF-alpha and IL-6 and low production of IFN-gamma, in comparison with the normal (N) and osteoarthrosis (OA) populations. The IL-2 secretion pattern is unique, arising from production followed by consumption. This production-consumption turnover is the most elevated in the RA group. The T cells are indeed activated in rheumatoid arthritis but regulatory events suppress some of their functions. A correlation was found between the inflammatory proteins and mediators of cellular immunity and macrophagic function: IL-1 beta and the sedimentation rate; IL-6 and fibrinogen; TNF-alpha and the number of blood monocytes. The secretion of OA-stimulated whole blood cells was similar to RA for two monokines (overproduction of TNF-alpha and IL-6) and different for IL-1 beta, not different from normal in OA. Stimulated whole blood cell cytokine secretion profile from RA and OA groups, was the same as previously observed in synovial fluid.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole blood: II. Application to rheumatoid arthritis and osteoarthritis. 129 40

The effect of eosinophil cationic protein (ECP) upon proliferation of human B cell lines or purified B cells was studied. ECP inhibited proliferation of the human lymphoblastoid cell lines CBL and GM-1056 at doses of 0.1-5 ng/mL during 2-4 days of culture. The inhibitory effect of ECP was reversible and not due to toxic damage. Moreover, inhibition could be blocked by anti-ECP serum while the control serum failed to do so. Of various cytokines tested--including interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6; interferon (IFN)-alpha or IFN-gamma--IL-4 reduced the inhibition, while other cytokines failed to do so. The reduction of inhibition was specific to IL-4 since reduction by IL-4 was blocked by anti-IL-4 antibody but not by the control antibody. ECP also inhibited proliferation of tonsillar small resting B cells stimulated with anti-mu antibody plus low molecular weight B-cell growth factor (BCGF) or of large activated B cells. In contrast, ECP had no effect on proliferation of unstimulated small resting B cells. This inhibition was also reduced by IL-4 specifically. These results indicate that ECP may also act as a B-cell regulating factor.
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PMID:Human B-cell growth-inhibitory activity of eosinophil cationic protein. 130 27

In order to investigate the relationships between cytokine production and arthritic disease we have determined the concentrations of immunoreactive interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, tumour necrosis factor-alpha (TNF-alpha), interferon-alpha (IFN-alpha), IFN-gamma, and soluble IL-2-receptor (sIL-2R), as well as bioactive IL-1 and IL-6, in synovial fluids (SF) and plasma of patients with a variety of arthritides. Careful assay revealed only minimal concentrations of IL-1, particularly its biologically active form, in SF. No IL-1 was detectable in the plasma of patients that had IL-1 in their SF. Concentrations of both immunoreactive IL-1 beta and TNF-alpha in SF of rheumatoid arthritis (RA) patients were significantly higher than those in SF from patients with other inflammatory arthritides or osteoarthritis (OA). IL-6 and sIL-2R concentrations in both SF and plasma were higher in RA patients than in OA patients, and were significantly correlated. Approximately half of the SF from patients with all arthropathies contained detectable IFN-alpha, whilst IFN-Y was present in less than 10%. There were significant associations between IL-6, sIL-2R, IL-1 beta, TNF-alpha and IFN-alpha. The concentration of these cytokines, where detectable, was also related to leukocyte counts in the SF, as well as to parameters assessing local and systemic disease activity. Although IL-6 was the cytokine most clearly related to other cytokines, and to parameters assessing disease activity, the relationship between general articular disease activity and IL-6 was only evident in patients with arthropathies other than rheumatoid arthritis.
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PMID:Cytokine inter-relationships and their association with disease activity in arthritis. 846 37

The IgE synthesis is regulated by a system of immunocompetent cells (B and T lymphocytes) and cytokines (IL-4, IFN gamma, IL-2, IL-5, IL-6) produced by T cells as a response to antigenic stimuli. IL-4 alone, or associated with other cytokines, determines the CD23+ receptor (FCERII) expression on monocytes-macrophages, eosinophiles, platelets, epidermidis Langerhans cells and B lymphocytes surfaces, inducing its cleavage in a Soluble Factor (IgE-BF), that increases the IgE synthesis. IFN-gamma, on the other hand, plays an inhibitory role on T-dependent phenomena, IL-4-mediated. In patients affected by atopic diseases, associated with oculorhinites, dermatitis and hyper-IgE syndrome, are found high serum levels of IgE, eosinophiles, and a large number of CD23+ cells: this indicates the hyper-reactivity of the IgE system and the IL-4 overproduction.
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PMID:[The IgE system]. 130 59

To characterize the requirements for the induction of an anergic state in immunocompetent cells we examined the effect of an increase in intracellular calcium concentration on the subsequent responsiveness of cytolytic T cells to antigenic stimulation in vitro. Pretreatment of a murine cytolytic T cell clone with the calcium-ionophore A23187 resulted in the induction of an anergic state characterized by a decrease in cytolytic activity and granule exocytosis upon Ag-specific stimulation. Furthermore, IFN-gamma synthesis declined whereas de novo synthesis of a yet unidentified protein with a molecular mass of 33 kDa as well as proliferative response of cells in response to exogenous IL-2 were unaffected. This state of partial unresponsiveness 1) could be prevented by concomitant pretreatment of cells with cyclosporin A or protein synthesis inhibitors and 2) was reversible within 48 h. Biochemical analysis of TCR-induced intracellular activation revealed a block in signal transduction before the activation of protein kinase C because cellular unresponsiveness could be bypassed by the phorbol ester PMA plus the calcium-ionophore A23187. However, phosphatidylinositol turnover was markedly inhibited in unresponsive cells that also did not show a calcium influx on stimulation with concanavalin A. We conclude that a rise in intracellular calcium in cytolytic T cells might not only be necessary for cellular activation but may also trigger the induction of a partial unresponsiveness to antigenic stimulation due to an inhibition in the early phase of signal transduction.
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PMID:Functional and biochemical characterization of a calcium-ionophore-induced state of unresponsiveness in a cytolytic T cell clone. 131 47

The effects of different recombinant human cytokines and cytokine inhibitors were compared in a culture system in which cell contact with mutant EL-4 thymoma cells of murine origin efficiently stimulates human B cell proliferation and Ig secretion in conjunction with human T cell supernatant. IL-1 alpha, IL-1 beta, TNF-alpha, and IL-2 co-stimulated B cell proliferation and IgM, IgG, and IgA secretion, whereas IL-3, IL-4, IL-5, IL-6, IFN-gamma, or GM-CSF had weak or no activity in this regard. In contrast, TGF-beta 1 was strongly inhibitory. A very strict hierarchy of cytokine interactions was found in that IL-1 was necessary to induce TNF-alpha responsiveness, and TNF-alpha the IL-2 responsiveness, of the B cells. Most likely the small number of starting B cells in the present assay (300 FACS-separated B cells/200 microliters) minimized the effects of autocrine B cell factors. IL-4 together with IL-1 induced IgE secretion, and the IgE secretion was further increased by TNF-alpha. IFN-gamma had no modulatory effect on the IL-4 dependent IgE response in this system. Pretreatment of B cells with IL-1R antagonist (IL-1ra, which binds to IL-1R) or addition of soluble TNF receptor type 1 (sTNF-R55, which binds to TNF) completely inhibited the IL-1 or TNF-alpha effects, respectively. This occurred in a specific manner; the inhibition was reversed by a large excess of cytokine. IL-1ra also inhibited a B cell response induced by PMA-preactivated EL-4 cells alone. Because B cells responding to such preactivated EL-4 cells did not acquire TNF-alpha responsiveness, no IL-1 was apparently involved under this assay condition. It appears, therefore, 1) that IL-1ra can act on B cells and 2) that this antagonist may not only block IL-1R, but may provide a direct or indirect inhibitory signal interfering even with IL-1-independent B cell activation.
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PMID:Effects of eleven cytokines and of IL-1 and tumor necrosis factor inhibitors in a human B cell assay. 131 59

We investigated a broad spectrum of immunoactive mediators in a mouse model of influenza. ICR mice (4-5 wk old) that were infected with a 10 LD50 dose of influenza A/PR8/34 virus died after 6 days without evidence of bacterial superinfection. Maximal virus titers were reached by day 2 postinfection, whereas the multifocal pneumonia with mononuclear cell infiltration reached its maximum at the end of infection. We measured the cytokines IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-6, IFN-gamma, TNF-alpha, granulocyte (G)/macrophage (M)-CSF, G-CSF, M-CSF, and the lipid mediators leukotriene B4 and platelet-activating factor in the cellfree bronchoalveolar lavage fluid of mice during infection. We found an early increase of IL-1 alpha, IL-1 beta, IL-6, TNF-alpha, GM-CSF, IFN-gamma, and leukotriene B4. Levels of these factors peaked between 36 h and day 3 postinfection, with the exception of IL-6 that remained at elevated levels throughout infection. G-CSF and M-CSF increased slowly and reached a maximum by day 5 postinfection. We were unable to detect IL-2, IL-3, or IL-4. PAF remained at the same level throughout infection. Our results suggest that lung-resident cells, and possibly the alveolar macrophages, participate actively in the onset of the inflammatory response against the invading virus. The inability to detect the T cell products IL-2, IL-3, and IL-4 was unexpected considering the role of T cells in the elimination of the virus in infected mice. Our observation confirms thus earlier findings about the inability of specific T cell clones to elicit an unspecific antiviral effect.
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PMID:A kinetic study of immune mediators in the lungs of mice infected with influenza A virus. 132 55

To study the interaction of lymphocytes and macrophages in the control of extracellular matrix turnover, we determined the effects of several soluble T cell products on mononuclear phagocyte production of metalloproteinases. Cytokines including IL-2, IL-4, IL-6, tumor necrosis factor alpha (TNF alpha), GM-CSF, and IFN-gamma were each tested for capacity to modulate macrophage metalloproteinase and tissue inhibitor of metalloproteinases (TIMP) expression. The addition of IL-4 to cells cultured under basal conditions caused a dose-dependent suppression in the release of 92-kD type IV collagenase without affecting TIMP production. 92-kD enzyme secretion was inhibited by 50% with 1-2 ng/ml of IL-4 and by 90% with 10 ng/ml of IL-4. When cells were first exposed to killed Staphylococcus aureus to induce metalloproteinase production, IL-4 potently blocked the stimulated release of both interstitial collagenase and 92-kD type IV collagenase, again without effect upon TIMP. Metabolic labeling experiments and Northern hybridizations demonstrated that IL-4 exerted its action at a pretranslational level. Furthermore, IL-4 possessed the capacity to inhibit metalloproteinase expression even in the relatively immature peripheral blood monocyte. As reported previously (Shapiro, S. D., E. J. Campbell, D. K. Kobayashi, and H. G. Welgus. 1990. J. Clin. Invest. 86:1204), IFN-gamma suppressed constitutive macrophage production of 92-kD type IV collagenase. Despite the frequent antagonism observed between IL-4 and IFN-gamma in other systems, the combination of these two agents lowered metalloproteinase biosynthesis dramatically, whereas IL-4 opposed the IFN-gamma-stimulated production of cytokines (IL-1 and TNF alpha). IL-6 had only minimal effect upon metalloproteinase production, but appeared to specifically augment TIMP release. In summary, cytokines released by activated T cells may profoundly reduce the capacity of the macrophage to mediate extracellular matrix degradation.
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PMID:Suppression of metalloproteinase biosynthesis in human alveolar macrophages by interleukin-4. 132 38


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