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

Interleukin-2 (IL-2) specifically recognizes high-mannose type glycans with five or six mannosyl residues. To determine whether the carbohydrate recognition activity of IL-2 contributes to its physiological activity, the inhibitory effects of high-mannose type glycans on IL-2-dependent CTLL-2 cell proliferation were investigated. Man(5)GlcNAc(2)Asn added to CTLL-2 cell cultures inhibited not only phosphorylation of tyrosine kinases but also IL-2-dependent cell proliferation. We found that a complex of IL-2, IL-2 receptor alpha, beta, gamma subunits, and tyrosine kinases was formed in rhIL-2-stimulated CTLL-2 cells. Among the components of this complex, only the IL-2 receptor alpha subunit was stained with Galanthus nivalis agglutinin which specifically recognizes high-mannose type glycans. This staining was diminished after digestion of the glycans with endo-beta-N-acetylglucosaminidase H or D, suggesting that at least a N-glycan containing Man(5)GlcNAc(2) is linked to the extracellular portion of the IL-2 receptor alpha subunit. Our findings indicate that IL-2 binds the IL-2 receptor alpha subunit through Man(5)GlcNAc(2) and a specific peptide sequence on the surface of CTLL-2 cells. When IL-2 binds to the IL-2Ralpha subunit, this may trigger formation of the high affinity complex of IL-2-IL-2Ralpha, -beta, and -gamma subunits, leading to cellular signaling.
 ...
PMID:Interleukin-2 carbohydrate recognition modulates CTLL-2 cell proliferation. 1107 50

Interleukin-2 (IL-2) is a cytokine with important roles in the immune system. IL-2 initially binds a high mannose-type glycan and a specific peptide sequence of the IL-2 receptor alpha-subunit and sequentially forms a high affinity complex of IL-2.IL-2 receptor alpha-, beta-, and gamma-subunits. This formation induces cellular signaling and cell proliferation (Fukushima, K., and Yamashita, K. (2001) J. Biol. Chem. 276, 7351-7356). To determine the carbohydrate-binding site of IL-2, we prepared wild-type and point-mutated (35)S-IL-2 by an in vitro transcription and translation method. We found that wild-type (35)S-IL-2 tends to form a dimer spontaneously, and the dimeric form has both carbohydrate recognition activity and cell proliferation activity. Moreover, substitution of Asn-26 in IL-2 with Gln or Asp conserved the dimeric form and affected the carbohydrate recognition activities in correspondence with the cell proliferation activities, suggesting that Asn-26 in IL-2 is involved in the carbohydrate recognition site. These results suggest that the carbohydrate recognition of IL-2 dimer triggers formation of high affinity complex (IL-2.IL-2Ralpha, -beta, -gamma)(2), and the hetero-octamer stimulates IL-2-dependent T-cell proliferation by intensifying cellular signaling.
 ...
PMID:Carbohydrate recognition site of interleukin-2 in relation to cell proliferation. 1139 Mar 92

Interleukin-2 (IL-2) regulates the proliferation and homeostasis of lymphocytes through the coordinated activation of distinct signaling pathways. Deletion of the acidic-rich domain of the IL-2 receptor beta chain (IL-2Rbeta) prevents association of Src tyrosine kinases to the receptor, as well as IL-2-induced Akt activation. Cells bearing this deletion (BafbetaDeltaA) maintain full proliferation in response to IL-2 both in vivo and in vitro, suggesting that those pathways are dispensable for this important function of IL-2. In this study, we re-examined phosphatidylinositol-3 kinase (PI3K) activation in BafbetaDeltaA cells and found that, in BaF/3 IL-2RbetaDeltaA cells, deletion of the acidic domain induced constitutive activation of the receptor-associated PI3K activity. This, in turn, was responsible for the higher basal Akt activity observed in cells expressing this deletion. Based on these data, and since pharmacological abrogation of PI3K activity prevented IL-2-driven cell proliferation of BafbetaDeltaA cells, we conclude that the PI3K/Akt pathway is still functionally relevant in cells bearing this mutation. Moreover, we show that the PI3K-induced signals are, at least in part, responsible for c-myc expression. In conclusion, we have used this model to better identify those signals that are integral components of the molecular mechanisms responsible for IL-2-regulated cell proliferation.
 ...
PMID:Deletion of the acidic-rich domain of the IL-2Rbeta chain increases receptor-associated PI3K activity. 1143 34

Interleukin-2 (IL-2) plays an important role in adaptive immune responses. These responses differ between females and males and may be due to the sex steroid estrogen. In this investigation we show that estrogen suppresses IL-2 production from activated peripheral blood T cells and CD4+ T cell lines at the transcriptional level. Suppression of IL-2 occurred at short term, high 17-beta-estradiol concentrations as well as longer term lower 17-beta-estradiol concentrations. In CD4+ Jurkat T cells, suppression of IL-2 was associated with decreased nuclear binding of two important IL-2 promoter transcription factors: NFkappaB and AP-1. The decreased nuclear binding of NFkappaB occurred in the setting of estrogen-induced increases in IkappaBalpha protein levels, an important inhibitor of NFkappaB nuclear translocation. 17-beta-Estradiol was also shown to inhibit IL-2 receptor (IL-2R) expression in activated peripheral blood T cells. Estrogen-induced suppression of IL-2 and its receptor may have many ramifications for our understanding of immune and autoimmune sexual dichotomies, immune responses during pregnancy, and potential therapeutic intervention with hormone agonists and antagonists.
 ...
PMID:17-beta-estradiol suppresses IL-2 and IL-2 receptor. 1149 93

Interleukin-2-deficient (IL-2-/-) mice develop a spontaneous, progressive, CD4+ T-cell-mediated colitis with an age-related decrease in the number of B lymphocytes. The aim of this study was to determine the mechanisms of B-cell loss in IL-2-/- mice. Serum immunoglobulin G1 (IgG1) levels in 8-week-old IL-2-/- mice were above normal but then decreased dramatically with advancing age. Between 8 and 11 weeks of age, the number of B-cell progenitors (B220+ IgM-) in the bone marrow of IL-2-/- mice was less than half of those in IL-2+/+ littermates. By 22 weeks of age, very few progenitor cells remained in the bone marrow of most mice, and spleens were almost devoid of B cells. Likewise, B1 cells were not present in the peritoneal cavity of aged IL-2-/- mice. Flow cytometry analysis of B-cell differentiation in the bone marrow suggested a progressive loss of B cells from the most mature to the least mature stages, which was not dependent on IL-2 receptor-alpha (IL-2Ralpha) expression. B cells transferred from normal animals had similar survival rates in IL-2-/- and wild-type mice. We conclude that conventional B cells in older IL-2-/- mice are lost by attrition owing to a derangement in B-cell development. Because B1 cells are less dependent on the bone marrow, a separate mechanism for their loss is suggested.
 ...
PMID:Disrupted B-lymphocyte development and survival in interleukin-2-deficient mice. 1168 51

Interleukin-2 (IL-2) plays a major role in the proliferation of cell populations during an immune reaction. The beta(c) and gamma(c) subunits of the IL-2 receptor (IL-2R) are sufficient and necessary for signal transduction. Despite lacking known catalytic domains, receptor engagement leads to the activation of a diverse array protein tyrosine kinases (PTKs). In resting or anergised T cells, Jak3 is not activated. Signals arising from the PROX domain of the gamma(c) subunit activate p56(lck) (lck) leading to the induction of anti-apoptotic mechanisms. When Jak3 is activated, in primed T cells, other PTKs predominantly mediate the induction of anti-apoptotic mechanisms and drive cellular proliferation. This review intends to suggest a role for these differences within the context of the immune system.
 ...
PMID:Alternate signalling pathways from the interleukin-2 receptor. 1175 Aug 78

Interleukin-2 (IL-2) belongs to a class of soluble, regulatory proteins known as cytokines. It is a 133 amino acid glycoprotein secreted by T(H) lymphocytes and other cells following activation by antigens, mitogens and other cytokines. It stimulates the proliferation and cytotoxicity of T lymphocytes. It also enhances the microbicidal and cytotoxic activities of NK cells, B lymphocytes, macrophages and monocytes. IL-2 can now be produced in unlimited quantities by recombinant DNA technology and used therapeutically to modulate the immune system in a number of diseases. A number of different studies have demonstrated its therapeutic value in HIV +ve and AIDS patients. It has been approved by US-FDA for treatment of metastatic renal cell carcinoma (RCC) and metastatic melanoma. Routine detection of soluble IL-2 receptor in blood could be useful as a diagnostic marker in some autoimmune diseases. Agents that antagonize IL-2 find application as immunosuppressants. The main adverse effect of IL-2 is capillary leak syndrome caused by increased capillary permeability and extravasation of fluid. In days to come, IL-2 is likely to play an increasingly important role in management of viral infections, malignancies and a number of other diseases conditions.
 ...
PMID:Interleukin-2 as a therapeutic agent. 1183 57

Interleukin-2 (IL-2) is a T cell derived cytokine that leads to a sustained expansion of the CD4+ T cell pool when given as 5-day cycles approximately every 8 weeks. An extensive series of phase I/II studies have been carried out and have leaded to the initiation of two phase III trials that are currently enrolling patients in 23 countries. Studies of the mechanisms of action have revealed that IL-2 is capable of inducing the polyclonal proliferation of CD4+ and CD8+ T cells, even in the absence of expression of the high affinity IL-2 receptor. While IL-2 leads to a 6-fold increase in T cell proliferation and a 2-fold increase in T cell death, the primary mechanism of action leading to expansion of the CD4+ T cell pool appears to be an increase in CD4+ T cell survival. While early work focused on the ability of IL-2 to exert these effects in patients with relatively early stages of HIV infection, more recent work, in the setting of HAART, indicates that these effects may be seen at all stages of HIV disease. The results of the phase III studies should provide an answer to the question of whether or not this is a strategy that will be of clinical benefit.
 ...
PMID:The potential role of interleukin-2 in patients with HIV infection. 1199 83

Interleukin-2 induces heterodimerization of the IL-2 receptor beta and gamma subunits. This study addresses a role of the Shb adapter protein in IL-2 receptor signaling in T and NK cells. The IL-2Rbeta and gamma chains were found to co-immunoprecipitate with Shb, when each alone was co-expressed with Shb in COS cells. Using fusion proteins, the Shb SH2 domain was found to associate in a phosphotyrosine-dependent manner with the IL-2 receptor beta and gamma subunits upon IL-2 stimulation in primary T cells and the NK cell line NK-92. The main binding site of the Shb SH2 domain was phosphorylated Tyr-510 in the IL-2Rbeta chain. Shb was also phosphorylated upon IL-2 stimulation when overexpressed together with IL-2Rbeta (in pre-B cells, which express the gamma chain constitutively). These cells were also less apoptotic in the presence of IL-2 than cells overexpressing a mutant Shb (with a defect SH2 domain) or cells expressing a mutant IL-2Rbeta, with the Shb binding sites mutated to phenylalanine (Y392F, Y510F). JAK1 and JAK3 were also found to associate with Shb, but in contrast to the Shb-IL-2 receptor association, JAK1 and 3 appear to associate with the proline-rich regions of Shb. In conclusion, Shb links the IL-2 receptor to other signaling proteins and mediates the regulation of apoptosis in the presence of IL-2.
 ...
PMID:IL-2 receptor signaling through the Shb adapter protein in T and NK cells. 1220 Jan 37

Interleukin-2 (IL-2) prevents cell apoptosis and promotes survival, but the involved mechanisms have not been completely defined. Although phosphatidylinositide 3-kinase (PI 3-kinase) has been implicated in IL-2-mediated survival mechanisms, none of the 3 chains of the IL-2 receptor (IL-2R) expresses a binding site for PI 3-kinase. However, IL-2Rbeta does express a Syk-binding motif. By using an IL-2-dependent natural killer (NK) cell line, followed by validation of the results in fresh human NK cells, we identified Syk as a critical effector essential for IL-2-mediated prosurvival signaling in NK cells. Down-regulation of Syk by piceatannol treatment impaired NK cellular viability and induced prominent apoptosis as effectively as suppression of PI 3-kinase function by LY294002. Expression of kinase-deficient Syk or pretreatment with piceatannol markedly suppressed IL-2-stimulated activation of PI 3-kinase and Akt, demonstrating that Syk is upstream of PI 3-kinase and Akt. However, constitutively active PI 3-kinase reversed this loss of Akt function caused by kinase-deficient Syk or piceatannol. Thus, Syk appears to regulate PI 3-kinase, which controls Akt activity during IL-2 stimulation. More important, we observed Rac1 activation by IL-2 and found that it mediated PI 3-kinase activation of Akt. This conclusion came from experiments in which dominant-negative Rac1 significantly decreased IL-2-induced Akt activation, whereas constitutively active Rac1 reelevated Akt activity not only in Syk-impaired but also in PI 3-kinase-impaired NK cells. These results constitute the first report of a Syk --> PI3K --> Rac1 --> Akt signal cascade controlled by IL-2 that mediates NK cell survival.
 ...
PMID:Regulation of Akt-dependent cell survival by Syk and Rac. 1239 31


<< Previous 1 2 3 4 5 6 7 8 9 10