Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental infections of mice with the African trypanosome Trypanosoma brucei lead to a profound state of T-cell unresponsiveness in the lymph node cell (LNC) compartment. This suppression is mediated by macrophage-like cells which inhibit interleukin 2 (IL-2) secretion and down-regulate IL-2 receptor expression (M. Sileghem, A. Darji, R. Hamers, M. Van de Winkel, and P. De Baetselier, Eur. J. Immunol. 19:829-835, 1989). Similar suppressive cells can be generated in vitro by pulsing 2C11-12 macrophage hybridoma cells with opsonized T. brucei parasites (2C11-12P cells). Cocultures of 2C11-12P cells and LNCs secrete higher levels of gamma interferon (IFN-gamma), and the hyperproduction of IFN-gamma was found to be confined to CD8+ lymphoid cells. Elimination of CD8+ cells from cocultures of 2C11-12P cells and LNCs restores the T-cell proliferative response. Furthermore, addition of neutralizing anti-IFN-gamma antibodies to the cocultures reduces the level of suppression and concomitantly restores the level of IL-2 receptor expression. Hence, IFN-gamma plays a cardinal role in this in vitro model for T. brucei-elicited immunosuppression. Cocultures of LNCs and 2C11-12P cells in a two-chamber culture system further demonstrated that cell-cell contact is required for hyperproduction of IFN-gamma and, moreover, that IFN-gamma cooperates with a 2C11-12P-derived diffusible factor to exert its suppressive activity. Finally, tumor necrosis factor alpha (TNF-alpha produced by 2C11-12P cells was found to be implicated in the hyperproduction of IFN-gamma, since addition of neutralizing anti-TNF-alpha antibodies to cocultures reduced the level of suppression and concomitantly abrogated the hyperproduction of IFN-gamma. Collectively, our findings indicate that T. brucei-elicited suppressive 2C11-12 macrophage cells differentially influence T-cell subpopulations: (i) CD8+ cells are signaled via cell-cell contact to produce IFN-gamma, and TNF-alpha is implicated in this process, and (ii) locally produced IFN-gamma and macrophage-released factors act in concert to inhibit CD4+ and CD8+ T-cell proliferative responses.
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PMID:In vitro simulation of immunosuppression caused by Trypanosoma brucei: active involvement of gamma interferon and tumor necrosis factor in the pathway of suppression. 867 90

The serum IL-1 beta, IL-2, IL-4, IL-6, IL-8, TNF-alpha and soluble IL-2 receptor levels were measured, and the presence of anti-Fc gamma receptor (Fc gamma R) antibodies was investigated in the sera of 18 patients with systemic sclerosis (SSc). An increase of TNF-alpha was detected in 8 of the 18 cases. II-1 beta was elevated in all the 18 patients. Both IL-2 and IL-4 were elevated in 7 cases. The IL-6 level was elevated in 17 patients, while IL-8 was increased in all cases. The soluble IL-2 receptor level was elevated in 11 patients. Fc gamma R-specific antibodies were detected in the sera of 6 patients, and there was a significant association between anti-Fc gamma R antibody positivity and IL-4 elevation. The presence of anti-Fc gamma R antibodies may influence several cell functions and may contribute to the remarkable variability of cytokine levels in SSc.
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PMID:Serum cytokine and anti-Fc gamma R autoantibody measurements in patients with systemic sclerosis. 872 84

To determine whether the liver plays an immunological role in certain extrahepatic disorders, we investigated the expression of interleukin (IL)-1 beta, IL-6, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha in 11 patients who had recovered from cholecystolithiasis, 12 patients with gastric cancer, 20 patients with chronic hepatitis, and 6 healthy controls. Cytokine mRNAs in the liver were detected by semiquantitative reverse transcribed-polymerase chain reaction. Serum cytokines and soluble IL-2 receptor (sIL-2R) were investigated by enzyme-linked immunosorbent assays. Increases in TNF-alpha, IL-6, IL-1 beta, and IFN-gamma mRNAs were found in the livers of patients with extrahepatic diseases. TNF-alpha and IL-6 peptides were increased in the sera of patients with gastric cancer. TNF-alpha in the sera and TNF-alpha mRNA in the liver were correlated in gastric cancer patients. Surprisingly, sIL-2R in the serum of gastric cancer patients was significantly higher than the level in healthy controls. Our findings suggest that the liver produces cytokines in reaction to extrahepatic lesions. Further, the increase in sIL-2R in gastric cancer patients indicates that malignancy may affect the immune network in vivo.
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PMID:Increased expression of cytokines in liver and serum in patients with extrahepatic diseases. 884 75

The objective was to investigate if the presence of the v-Ha-ras oncogene could induce immune changes different to the ones observed in normal mice. Therefore, we decided to use Oncomice, the transgenic mice with an activated v-Ha-ras oncogene under the control of the mouse mammary tumor virus-promoter, and their normal inbred counterparts, FVB mice. Both strains of mice were fed the Lieber-DeCarli liquid diet with ethanol or the isocaloric control diet and were injected daily with cocaine or saline. The percentage and absolute number of T and B lymphocytes in the spleen and thymus were determined. The in vitro production of TNF-alpha (tumor necrosis factor-alpha), IL-2 (interleukin-2) and IFN-gamma (interferon-gamma) by spleen cells, and the levels of serum sIL-2R (soluble IL-2 receptor) were also measured. Oncomice fed the Lieber-DeCarli ethanol diet or receiving either saline or cocaine injections presented a higher tumor incidence than Oncomice receiving the control diet. A reduced total number of thymocytes as well as absolute number of cells in all the subsets was found in Oncomice. Moreover, a decreased percentage of CD8+ cells was also observed in Oncomouse spleens. These features were even more marked in ethanol-treated Oncomice. Higher serum sIL-2R levels were observed in Oncomice, especially in mice treated with ethanol or cocaine. The results suggest that the oncogene product, P21ras, plays an important role in dysregulating the immune system and hence in favoring tumorigenesis.
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PMID:Effect of ethanol and cocaine treatment of the immune system of v-Ha-ras-transgenic mice. 889 4

Trypanosoma cruzi infection in humans and experimental animals often results in a chronic heart and gut inflammation and a dysfunction known as Chagas' disease. Previous studies have shown that the cellular infiltrate in the hearts of animals with chronic Chagas' disease consists mainly of CD8+ T cells. In this study, we have used immunohistochemical techniques to further characterize the immunological nature of chagasic heart lesions in three murine models of experimental Chagas' disease. Double-staining immunohistochemistry revealed that 10-30% of the infiltrating CD8+ T cells in the hearts of infected mice expressed the activation molecules, IL-2 receptor and CD44. In addition, large numbers of cells producing TNF-alpha, TGF-beta, IL-1 alpha, and IL-6 were consistently observed in the heart lesions, appearing during the acute infection and persisting throughout the chronic stage of infection (> 300 days). In contrast, IFN-gamma- and IL-10-producing cells were detected in relatively low numbers and only transiently between approximately 3 and 9 weeks postinfection. Cells producing IL-2, IL-4, and IL-5 were not observed in the hearts of mice at any point during the infection. The appearance of cytokine-producing cells in the hearts correlated with an increased local expression of class I and class II MHC molecules and adhesion molecules (ICAM-1, LFA-1, VLA-4, and VCAM-1). The results of this study suggest that the chronic inflammation in chagasic hearts is highly active and associated with a stable immunological pattern extending from the early acute stage of the infection through the late chronic stage. The pattern of cytokine production in heart is distinct from that observed in lymphoid organs and is not suggestive of an association between particular classes of cytokines and disease development. Instead it appears that both inflammatory and anti-inflammatory cytokines determine the pattern of the cellular response and the severity of disease in T. cruzi infection.
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PMID:Persistent production of inflammatory and anti-inflammatory cytokines and associated MHC and adhesion molecule expression at the site of infection and disease in experimental Trypanosoma cruzi infections. 893 70

The infiltration of pancreatic islets by mononuclear cells is the hallmark of the development of insulin dependent diabetes mellitus (IDDM) in the NOD mouse, an animal model for human IDDM. The aim, of this study was to correlate adhesion molecule expression with the degree of islet infiltration and to compare Th1- and Th2-driven islet inflammation. Cryostat sections of NOD mouse pancreata before and after diabetes development were analysed by semiquantitative immunohistochemistry. NOD mouse islets did not show the expression of ICAM-1, LFA-1, L-selectin and VCAM-1 prior to infiltration by mononuclear cells. Furthermore, islets with early stage insulitis (grade 1, periinsular location of small infiltrates) still were devoid of adhesion molecule expression. ICAM-1 and LFA-1 were first demonstrable in islets with strong periinsular infiltrates (insulitis grade 2) while L-selectin and VCAM-1 were only seen in islets with mild or strong intraislet infiltration (grade 3-4). Adhesion molecules were demonstrable in areas of macrophage and T-lymphocyte infiltrates but not in adjacent endocrine islet tissue. Islets of all infiltration stages contained Th2 lymphocytes (positive for IL-4). Substantial numbers of Th1 cells (positive for IFN-gamma, TNF-alpha, IL-2 and/or IL-2 receptor) were observed only after acceleration of diabetes development by a single injection of cyclophosphamide (250 mg/kg i.p.). Interestingly, the adhesion molecule expression pattern in islets with "Th1' versus "Th2 insulitis' was not different. In conclusion, the expression of adhesion molecules in islets during the development of autoimmune diabetes does not precede mononuclear infiltration but probably occurs in response to the activation of initial small infiltrates. ICAM-1 and LFA-1 expression is seen prior to L-selectin and VCAM-1. However, adhesion molecule expression during Th1 versus Th2 cell infiltration is very similar, suggesting similar adhesion molecule requirements of the two Th subsets.
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PMID:Differential expression of ICAM-1 and LFA-1 versus L-selectin and VCAM-1 in autoimmune insulitis of NOD mice and association with both Th1- and Th2-type infiltrates. 893 79

The methylxanthine derivative pentoxifylline (PTX) is an immunomodulatory agent with incompletely characterized effects on cytokine production. To analyse these effects and to delineate new combination strategies in immunotherapy, we have investigated immunomodulatory properties of PTX in combination with dexamethasone (DEX) or cyclosporin A (CsA). Stimulated human peripheral blood mononuclear cells were treated with clinically relevant concentrations of PTX (12.5-100 micrograms/ml), DEX (0.01-10 microM) or CsA (12.5-50 ng/ml), alone or in combination. With increasing doses of PTX the maximum supernatant titres of tumour necrosis factor (TNF)-alpha, interleukin (IL)-2 and interferon (IFN)-gamma decreased concomitantly, and all cultures co-treated with DEX showed synergism. Release of IL-6 was not consistently altered under PTX treatment. Similarly, PTX and CsA synergistically inhibited the release of IL-2, IFN-gamma and, to a lesser degree, TNF-alpha. Although PTX alone did not significantly reduce lymphoproliferation, both combinations of drugs synergistically inhibited this process. Furthermore, to demonstrate that the key mechanism of PTX-induced effects is an increase in intracellular cyclic adenosine 3':5'-monophosphate (cAMP) levels, identical experiments were performed using dibutyryl-cAMP instead of PTX. In cultures treated with PTX and DEX, expression of different cell receptors was analysed. Expression of IL-2 receptor (IL-2R) was reduced in cultures treated with PTX, and combination with DEX led to further reduction. Expression of intercellular adhesion molecule (ICAM)-1 and of leucocyte function antigen (LFA)-1 alpha was also synergistically reduced, though to a lesser degree. HLA-DR expression remained unchanged. In conclusion, we demonstrate that clinically relevant levels of PTX exert profound immunomodulatory effects in vitro, and that the combined treatment with DEX or CsA has synergistic effects.
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PMID:Pentoxifylline exerts synergistic immunomodulatory effects in combination with dexamethasone or cyclosporin A. 896 50

We determined in the peritoneal cavity (p.c.) of epithelial ovarian carcinoma patients during a 4-day treatment cycle of low-dose recombinant human interleukin-2 (rIL-2): (a) pharmacokinetics of IL-2, (b) endogenous cytokine production, and (c) numbers and percentages of peritoneal exudate lymphocytes. We administered 6 x 10(5) IU/m2 of rIL-2 (0.03 mg/m2 Proleukin rIL-2) intraperitoneally (i.p.) over 30 min on each of 4 days. One and one-half liters of D5 0.25 NS was injected i.p. before each rIL-2 infusion. Multiple peritoneal fluid samples were obtained from each of four patients on day 1 and day 4 for detection of IL-2, endogenous cytokines, and soluble IL-2 receptor (IL-2R-alpha). IL-2 concentrations in the peritoneal fluid were determined by bioassay and interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-10, transforming growth factor (TGF)-beta 2, and sIL-2R-alpha by enzyme-linked immunosorbent assay. Numbers of cells per microliter and lymphocyte subpopulation percentages after staining with a panel of monoclonal antibodies were determined on day 1, day 4, and subsequent off-treatment days. IL-2 disappearance in the p.c. was well described by a pharmacokinetic model having constant-rate infusion and biexponential disposition. About 90% of the IL-2 disappearance occurred during the beta-phase, during which IL-2 concentrations were sustained at approximately 10-30 ng/ml (day 1 and day 4) and the median t1/2 beta was 21.5 and 9.2 h on days 1 and 4, respectively. In four of four patients, p.c. production of IL-10 was observed on day 1 and day 4 (maximum 387 pg/ml). Maximum levels of IFN-gamma and sIL-2R-alpha were observed on day 4. (IFN-gamma 217 pg/ml; sIL2-R-alpha: 3486 U/ml). No increases in TNF-alpha or TGF-beta 2 were observed. Large increases in p.c. CD3+, CD4+, CD8+, CD16+, and CD56+ cells were observed. We conclude that biologically active levels of IL-2 are generated in p.c. fluids after i.p. administration of rIL-2 at 0.03 mg/m2.
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PMID:Immunopharmacology and cytokine production of a low-dose schedule of intraperitoneally administered human recombinant interleukin-2 in patients with advanced epithelial ovarian carcinoma. 904 64

Resting lymphocyte survival is dependent upon the expression of Bcl-2, yet the factors responsible for maintaining lymphocyte Bcl-2 protein expression in vivo are largely unknown. Natural killer (NK) cells are bone marrow-derived lymphocytes that constitutively express the beta and common gamma(c) subunits of the IL-2 receptor (R) as a heterodimer with intermediate affinity for IL-2. IL-15 also binds to IL-2Rbeta gamma(c) and is much more abundant in normal tissues than IL-2. Mice that lack the IL-2 gene have NK cells, whereas mice and humans that lack IL-2R gamma(c) do not have NK cells. Further, treatment of mice with an antibody directed against IL-2Rbeta results in a loss of the NK cell compartment. These data suggest that a cytokine other than IL-2, which binds to IL-2Rbeta gamma(c), is important for NK cell development and survival in vivo. In the current report, we show that the recently described IL-15R(alpha) subunit cooperates with IL-2Rbeta gamma(c) to transduce an intracellular signal at picomolar concentrations of IL-15. We demonstrate that resting human NK cells express IL-15R(alpha) mRNA and further, that picomolar amounts of IL-15 can sustain NK cell survival for up to 8 d in the absence of serum. NK cell survival was not sustained by other monocyte-derived factors (i.e., TNF-alpha, IL-1beta, IL-10, IL-12) nor by cytokines known to use gamma(c) for signaling (i.e., IL-4, IL-7, IL-9, IL- 13). One mechanism by which IL-15 promotes NK cell survival may involve the maintenance of Bcl-2 protein expression. Considering these functional properties of IL-15 and the fact that it is produced by bone marrow stromal cells and activated monocytes, we propose that IL-15 may function as an NK cell survival factor in vivo.
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PMID:A potential role for interleukin-15 in the regulation of human natural killer cell survival. 906 51

The in vitro mixed lymphocyte reaction (MLR) is a useful model to study alloresponsiveness to histocompatibility antigens. Secretion of different cytokine proteins in the supernatant of allo-MLR cultures has been reported in a few studies with no reference to results in auto-MLR. Since most cytokines are autocrine factors, their levels in the supernatant may not reflect the actual intracellular production. Therefore, we studied cytokine gene expression in auto- and allo-MLR by Northern dot blotting and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. mRNA for IL-beta and IL-8 was detected in both auto- and allo-MLR by Northern dot blotting. mRNA for IL-2, gamma-IFN, TNF-alpha, IL-4, IL-10 and IL-2 receptor (IL-2R) was not found by Northern dot blotting and could only be detected by RT-PCR. Expression of mRNA for IL-4, IL-10, TNF-alpha, gamma-IFN and IL-2R by RT-PCR analysis was seen in both auto- and allo-MLR. There was slightly increased expression of gamma-IFN, IL-2R and TNF-alpha in allo-MLR in comparison to auto-MLR. However, IL-2 was exclusively expressed in allo-MLR and was detected as early as 5 h of initiation of culture. These results indicate that mRNA expression for a number of cytokines can be seen in both auto- and allo-MLR using RT-PCR analysis. However, the consistent expression of IL-2 in the allo-MLR indicates that it is an important cytokine which discriminates an allo- from an autoresponse. These findings suggest that detection of IL-2 gene expression by RT-PCR may be useful for immune monitoring of allograft rejection.
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PMID:Selective expression of the interleukin-2 gene discriminates between the auto- and allo-mixed lymphocyte reaction. 910 32


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