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Titolo:
Differential regulation of CD3-and CD28-induced IL-2 and IFN-gamma production by a novel tyrosine kinase inhibitor XR774 from Cladosporium cf. cladosporioides
Autore:
Sadeghi, R; Depledge, P; Rawlins, P; Dhanjal, N; Manic, A; Wrigley, S; Foxwell, B; Moore, M;
Indirizzi:
Xenova Ltd, Slough SL1 4EF, Berks, England Xenova Ltd Slough Berks England SL1 4EF d, Slough SL1 4EF, Berks, England Mathilda & Terrance Kennedy Inst Rheumatol, London W6 8LW, England Mathilda & Terrance Kennedy Inst Rheumatol London England W6 8LW England
Titolo Testata:
INTERNATIONAL IMMUNOPHARMACOLOGY
fascicolo: 1, volume: 1, anno: 2001,
pagine: 33 - 48
SICI:
1567-5769(200101)1:1<33:DROCCI>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
CYTOKINE PRODUCTION; T-CELLS; CD28; PHOSPHORYLATION; ACTIVATION; PATHWAYS; RECEPTOR; SIGNALS; B7-2;
Keywords:
Cladosporium cf. cladosporioides immunosuppression; ansamycins;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
19
Recensione:
Indirizzi per estratti:
Indirizzo: Moore, M Xenova Ltd, 240 Bath Rd, Slough SL1 4EF, Berks, England Xenova Ltd 240 Bath Rd Slough Berks England SL1 4EF erks, England
Citazione:
R. Sadeghi et al., "Differential regulation of CD3-and CD28-induced IL-2 and IFN-gamma production by a novel tyrosine kinase inhibitor XR774 from Cladosporium cf. cladosporioides", INT IMMUNO, 1(1), 2001, pp. 33-48

Abstract

Inhibition of CD28 signalling after an immune response impedes T cell activation and can lead to immunosuppression. To identify inhibitors of anti-CD28 induced IL-2 production, a library of fungal metabolites was screened ina cell-based, high throughput assay. A reduced novel benzofluoranthene, tentatively named as (6bS, 7R, 8S)-7-methoxy- 4, 8, 9-trihydroxy- 1, 6b, 7, 8-tetrahydro-2 H-benzo[j] fluoranthen-3-one (XR774), from Cladosporium cf. cladosporioides, was isolated. XR774 inhibited IL-2 mRNA and protein expression induced by anti-CD28 and anti-CD3 but had no effect on IL-2 induction by PMA and ionomycin. Moreover, XR774 inhibited the activity of the tyrosinekinases, Fyn, Lck, Abl and epidermal growth factor receptor (EGFR) with nanomolar activity, whereas micromolar concentrations of XR774 were ineffective on the serine-threonine kinase, PKA. Kinetic analysis of Fyn kinase inhibition was consistent with XR774 as a competitive inhibitor with respect toATP. In peripheral blood mononuclear cells (PBMC), XR774 inhibited anti-CD3 andanti-CD28 induced IL-2 and IL-2R ru chain (CD25) expression but was consistently less active for inhibition of IFN-gamma production. On stimulation with PMA and anti-CD28, XR774 inhibited IL-2 production but had no effect onCD25 expression and enhanced IFN-gamma production. In contrast, the ansamycin, geldanamycin, inhibited both IL-2 and IFN-gamma production induced by anti-CD3 and anti-CD28 or PMA and anti-CD28. No significant associated cytotoxicity or inhibition of protein synthesis was observed at concentrations up to 14 muM Thus, XR774 represents a novel class of pharmacological agent with selective biological activities that distinguish it from other naturalproduct inhibitors, such as the ansamycins. (C) 2001 Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 02:08:08