Uncoupling of promitogenic and antiapoptotic functions of IL-2 by Smad-dependent TGF-beta signaling.
J Immunol
; 170(11): 5563-70, 2003 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-12759434
ABSTRACT
TGF-beta opposes proliferative signaling by IL-2 through mechanisms that remain incompletely defined. In a well-characterized CD8(+) T cell model using wild-type and mutated IL-2 receptors, we examined the effects of TGF-beta on distinct IL-2 signaling events in CD8(+) T cells. IL-2 induces c-myc, cyclin D2, and cyclin E in a redundant manner through the Shc and STAT5 pathways. TGF-beta inhibited the ability of either the Shc or STAT5 pathway to induce these genes, as well as T cell proliferation. The inhibitory effects of TGF-beta were reversed by expression of a dominant-negative form of Smad3. TGF-beta did not impair proximal signaling by Shc or STAT5, and induction of some downstream genes, including cytokine-inducible Src homology-2-containing protein (CIS), bcl-x(L), and bcl-2, was spared. Experiments with c-fos, cyclin D2, and CIS reporter genes revealed that promoter-proximal regulatory elements dictate the sensitivity of IL-2 target genes to inhibition by TGF-beta. By leaving the Shc and STAT5 pathways functional while inhibiting their target genes selectively, TGF-beta was found to uncouple the proliferative and antiapoptotic functions of IL-2. Thus, TGF-beta is not a simple antagonist of IL-2, but rather serves to qualitatively modify the IL-2 signal to create a unique pattern of gene expression that neither cytokine can induce independently.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Transativadores
/
Fator de Crescimento Transformador beta
/
Interleucina-2
/
Apoptose
/
Proteínas de Ligação a DNA
/
Proteínas do Leite
/
Mitógenos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2003
Tipo de documento:
Article
País de afiliação:
Estados Unidos