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Titolo:
Residual type 1 immunity in patients genetically deficient for interleukin12 receptor beta 1 (IL-12R beta 1): Evidence for an IL-12R beta 1-independent pathway of IL-12 responsiveness in human T cells
Autore:
Verhagen, CE; de Boer, T; Smits, HH; Verreck, FAW; Wierenga, EA; Kurimoto, M; Lammas, DA; Kumararatne, DS; Sanal, O; Kroon, FP; van Dissel, JT; Sinigaglia, F; Ottenhoff, THM;
Indirizzi:
LUMC, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands LUMC Leiden Netherlands NL-2300 RC nsfus, NL-2300 RC Leiden, Netherlands LUMC, Dept Infect Dis, NL-2300 RC Leiden, Netherlands LUMC Leiden Netherlands NL-2300 RC t Dis, NL-2300 RC Leiden, Netherlands Acad Med Ctr, Dept Cell Biol & Histol, NL-1105 AZ Amsterdam, Netherlands Acad Med Ctr Amsterdam Netherlands NL-1105 AZ AZ Amsterdam, Netherlands Hayashibara Biochem Labs, Fujisaki Inst, Okayama 7028006, Japan Hayashibara Biochem Labs Okayama Japan 7028006 t, Okayama 7028006, Japan Univ Birmingham, MRC, Ctr Immune Regulat, Birmingham, W Midlands, England Univ Birmingham Birmingham W Midlands England ngham, W Midlands, England Hacettepe Univ, Childrens Hosp, Div Immunol, TR-06100 Ankara, Turkey Hacettepe Univ Ankara Turkey TR-06100 v Immunol, TR-06100 Ankara, Turkey Roche Milano Rech, I-20132 Milan, Italy Roche Milano Rech Milan Italy I-20132 Milano Rech, I-20132 Milan, Italy
Titolo Testata:
JOURNAL OF EXPERIMENTAL MEDICINE
fascicolo: 4, volume: 192, anno: 2000,
pagine: 517 - 528
SICI:
0022-1007(20000821)192:4<517:RT1IIP>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACTIVATED PROTEIN-KINASE; INTERFERON-GAMMA-RECEPTOR; TH2 CELLS; TYROSINE PHOSPHORYLATION; CYTOKINE PRODUCTION; MYCOBACTERIAL INFECTION; IL-12-DEFICIENT MICE; SELECTIVE EXPRESSION; RESPONSES; STAT4;
Keywords:
mycobacteria; Th1; interleukin 12 (receptor); interleukin 18 (receptor); interferon-gamma;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
48
Recensione:
Indirizzi per estratti:
Indirizzo: Ottenhoff, THM LUMC, Dept Immunohematol & Blood Transfus, Albinusdreef 2,POB 9600, NL-2300 RC Leiden, Netherlands LUMC Albinusdreef 2,POB 9600 Leiden Netherlands NL-2300 RC
Citazione:
C.E. Verhagen et al., "Residual type 1 immunity in patients genetically deficient for interleukin12 receptor beta 1 (IL-12R beta 1): Evidence for an IL-12R beta 1-independent pathway of IL-12 responsiveness in human T cells", J EXP MED, 192(4), 2000, pp. 517-528

Abstract

Genetic lack of interleukin 12 receptor beta 1 (IL-12R beta 1) surface expression predisposes to severe infections by poorly pathogenic mycobacteria or Salmonella and causes strongly decreased, but not completely abrogated, interferon (IFN)-gamma production. To study IL-12R beta 1-independent residual IFN-gamma production, we have generated mycobacterium-specific T cell clones (TCCs) from IL-12R beta 1-deficient individuals. All TCCs displayed aT helper type 1 phenotype and the majority responded to IL-12 by increasedIFN-gamma production and proliferative responses upon activation. This response to IL-12 could be further augmented by exogenous IL-18. IL-12R beta 2was found to be: normally expressed in the absence of IL-12R beta 1, and could be upregulated by IFN-alpha. Expression of IL-12R beta 2 alone, however, was insufficient to induce signal transducer and activator of transcription (Stat)LF activation in response to IL-12, whereas IFN-alpha/IFN-alpha Rligation resulted in Stat4 activation in both control and IL-12R beta 1-deficient cells. IL-12 failed to upregulate cell surface expression of IL-18R, integrin alpha 6, and IL-12R beta 2 on IL-12R beta 2-deficient cells, whereas this was normal on control cells. IL-12-induced IFN-gamma production in IL-12R beta 1-deficient T cells could be inhibited by the p38 mitogen-activated protein kinase (MAP) kinase inhibitor SB203580 and the MAP kinase kinase (MEK) 1/2 inhibitor U0126, suggesting involvement of MAP kinases in this alternative, Stat4-independent, IL-12 signaling pathway. Collectively, these results indicate that IL-12 acts as a partial agonist in the absence of IL-12R beta 1. Moreover, the results reveal the presence of a novel IL-12R beta 2/Stat4-independent pathway of IL-12 responsiveness in activated human T cells involving MAP kinases. This pathway is likely toplay a role in the residual type 1 immunity in IL-12R beta 1 deficiency.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/12/20 alle ore 03:55:53