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)

Stimulation of highly purified primary T lymphocytes through CD2 and CD28 adhesion molecules induces a long-term proliferation, dependent on persistent autocrine secretion of interleukin 2 (IL-2), high and prolonged expression of inducible CD25/IL-2 receptor alpha chain (IL-2Ralpha), and secretion of growth factors such as the granulocyte-macrophage colony-stimulating factor (GM-CSF). CD28 costimulation appears to activate cytokine gene expression through conserved kappaB-related CD28 response (CD28RE) or cytokine 1 (CK-1) elements in addition to canonical NF-kappaB-binding sites. In this report, we assess: 1) the evolution of the expression, over an 8-day time period, of the Rel/NF-kappaB family of proteins in costimulated versus TcR/CD3-stimulated primary T cells; 2) the impact of changes on the in vitro occupancy of GM-CSF kappaB and CK-1, as well as IL-2Ralpha kappaB sites; and 3) the differential regulation of newly synthesized p65 and c-Rel by IkappaB proteins. We show that CD2+CD28 stimulation specifically induces, at maximal T cell proliferation phase, sustained nuclear overexpression of NFKB2 p52 and c-Rel subunits which might rely on long-lasting processing of p100 precursor for p52 and increased neosynthesis of c-Rel. This up-regulation correlates with sustained occupancy of GM-CSF kappaB and CK-1 elements by both proteins. Conversely, these subunits do not appear to bind to the IL-2Ralpha kappaB site. Costimulation, but not TcR/CD3 stimulation, appears supported by sustained down-regulation of both IkappaBalpha and -beta regulators. Furthermore, contrary to p65, c-Rel appears to display little affinity for p105, p100 and IkappaBalpha regulators.
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PMID:Temporal and subunit-specific modulations of the Rel/NF-kappaB transcription factors through CD28 costimulation. 926 7

Induction of NFkappaB is a highly regulated process requiring phosphorylation, ubiquitination, and proteasome-mediated degradation of the cytosolic inhibitor IkappaBalpha. Analyses of the regulation of IkappaBalpha in TNF-alpha-treated T lymphocytes from young and elderly donors revealed severely compromised degradation of IkappaBalpha in T cells from the elderly. Examination of activation-induced phosphorylation and ubiquitination of IkappaBalpha did not demonstrate any significant age-related alterations. However, examination of proteasome activity in these T cells using fluorogenic peptide assays revealed a significant age-related decline in chymotryptic activity. These results suggest that a decline in proteasome activity results in a failure to fully degrade IkappaBalpha in the elderly. This failure to degrade IkappaBalpha may underlie both the observed decrease in NFkappaB induction and the IL-2 receptor expression in TNF-treated T cells during aging. Thus, decreased proteasome-mediated degradation may be central to immune dysfunction that accompanies aging.
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PMID:Decreased proteasome-mediated degradation in T cells from the elderly: A role in immune senescence. 1008 85

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.
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PMID:17-beta-estradiol suppresses IL-2 and IL-2 receptor. 1149 93

T cell receptor-stimulated NF-kappaB activation requires CARMA1 and is negatively regulated by the deubiquitinase CYLD. Recent studies suggest that CARMA1 regulates regulatory T cell (Treg) development, although the role of NF-kappaB in this event is incompletely understood. We show that CYLD deficiency causes constitutive NF-kappaB activation in thymocytes, which is associated with enhanced frequency of Treg cells. The NF-kappaB activation in CYLD-deficient thymocytes is independent of CARMA1, because the NF-kappaB activation was also detected in CYLD/CARMA1 double knock-out thymocytes. Interestingly, although loss of CYLD causes NF-kappaB activation in the CARMA1-deficient thymocytes, the CYLD deficiency fails to rescue the defect of CARMA1 knock-out mice in Treg development. Furthermore, inhibition of canonical NF-kappaB by an IkappaBalpha transgene only partially inhibits Treg development. We demonstrate that CARMA1 regulates IL-2 receptor signaling and controls the IL-2-stimulated maturation of Treg precursors to mature Tregs. These results suggest that the role of CARMA1 in Treg regulation involves both NF-kappaB activation and IL-2 receptor signaling.
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PMID:CARMA1 regulation of regulatory T cell development involves modulation of interleukin-2 receptor signaling. 2023 21