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1.
Proc Natl Acad Sci U S A ; 95(16): 9454-8, 1998 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-9689101

RESUMO

Interleukin 4 (IL-4) is a pleiotropic cytokine. Of the cell types responsive to IL-4, T cells express one IL-4 receptor (IL-4R) type, IL-4Ralpha/IL-2Rgamma (class I IL-4R), whereas endothelial cells express another type, IL-4Ralpha/IL-13Ralpha (class II IL-4R). It was hypothesized that IL-4 variants could be generated that would be selective for cell types expressing the different IL-4Rs. A series of IL-4 muteins were generated that were substituted in the region of IL-4 implicated in interactions with IL-2Rgamma. These muteins were evaluated in T cell and endothelial cell assays. One of these muteins, containing the mutation Arg-121 to Glu (IL-4/R121E), exhibited complete biological selectivity for T cells, B cells, and monocytes, but showed no activity on endothelial cells. Receptor binding studies indicated that IL-4/R121E retained physical interaction with IL-2Rgamma but not IL-13Ralpha; consistent with this observation, IL-4/R121E was an antagonist of IL-4-induced activity on endothelial cells. IL-4/R121E exhibits a spectrum of activities in vitro that suggest utility in the treatment of certain autoimmune diseases.


Assuntos
Interleucina-4/agonistas , Linfócitos B/imunologia , Linfócitos B/metabolismo , Ligação Competitiva , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Interleucina-4/metabolismo , Receptores de Interleucina-4/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
2.
Cell Growth Differ ; 7(11): 1535-44, 1996 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8930403

RESUMO

This study examined the role of transforming growth factor beta 1 (TGF-beta 1) in monocytic differentiation of hematopoietic cells. TGF-beta 1 and retinoic acid (RA) inhibited HL-60 cell growth in a dose-dependent fashion. Treatment of HL-60 cells with a combination of TGF-beta 1 and a 50% optimal dose of RA (RA + TGF-beta 1) resulted in increased growth suppression compared to the individual treatments. Morphological studies revealed that TGF-beta 1 induced promonocytic differentiation (68%), RA induced granulocytic differentiation (98%), and RA + TGF-beta 1 induced monocytic (54%) and granulocytic (46%) differentiation of HL-60 cells. Induction of the monocyte-specific marker, nonspecific esterase, was markedly increased by TGF-beta 1 and RA + TGF-beta 1 treatment but not by RA treatment. Both TGF-beta 1 treatment and RA treatment increased TGF-beta ligand and TGF-beta receptor protein and mRNA levels. To determine whether RA mediated HL-60 cell growth inhibition and differentiation through the autocrine expression of TGF-beta 1, experiments using TGF-beta 1 antisense oligonucleotides or TGF-beta 1-neutralizing antibodies were conducted. TGF-beta 1 antisense oligonucleotides and neutralizing antibodies partially blocked RA-induced inhibition of proliferation, and TGF-beta 1 antisense oligonucleotides reversed RA-induced granulocytic maturation, demonstrating that RA signals autocrine expression of TGF-beta 1 and TGF-beta receptors. The effect of TGF-beta 1 on normal hematopoiesis was also studied using primary human fetal liver cells. TGF-beta 1 alone and in the presence of interleukin 3 promoted macrophage differentiation of primitive fetal liver cells. Cell surface expression of the monocyte/macrophage-specific marker c-fms was increased 3.1-fold following TGF-beta 1 treatment. In addition, TGF-beta 1-treated cells displayed a 51% increase in phagocytosis as compared to interleukin 3-treated control cells. These studies define a role for TGF-beta 1 in the autocrine and paracrine regulation of monocyte/macrophage differentiation.


Assuntos
Hematopoese/fisiologia , Monócitos/citologia , Receptores de Fatores de Crescimento Transformadores beta/genética , Fator de Crescimento Transformador beta/farmacologia , Tretinoína/farmacologia , Biomarcadores , Diferenciação Celular , Divisão Celular , Células Cultivadas , Esterases/análise , Expressão Gênica , Granulócitos/citologia , Células HL-60 , Humanos , Interleucina-3/farmacologia , Fígado/citologia , Fígado/embriologia , Oligonucleotídeos Antissenso , Fagocitose , Receptor de Fator Estimulador de Colônias de Macrófagos/análise , Receptores de Fatores de Crescimento Transformadores beta/análise
3.
Oncogene ; 13(7): 1499-509, 1996 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-8875988

RESUMO

Transformation of interleukin-3 dependent (IL-3) 32D-123 myeloid cells by p120-v-Abl produced the factor-independent 32D-abl cell line. In 32D-abl cells, myc expression was found to be significantly higher than in the parental cells and was correlated with increased E2F-1 protein expression and DNA binding ability. Surprisingly, in 32D-abl cells, TGF-beta1, a potent G1/S inhibitor of 32D-123 and 32D-abl cell growth, increased E2F transactivation as shown by increased c-myc promoter-CAT and GAL4-E2F-1 activity. In addition, TGF-beta1 was also found to increase E2F-1 protein levels but had no effect on steady-state retinoblastoma (RB) protein levels or phosphorylation state. In the absence of TGF-beta1, transient expression of RB in v-Abl expressing cells resulted in decreased c-myc transcription, inhibition of GAL4-E2F-1 driven transactivation and inhibition of cellular proliferation. RB and v-Abl were found to physically associate in vivo and in vitro via v-Abl's ATP binding region. In summary, these studies established that in myeloid cells: (1) v-Abl binds RB resulting in increased E2F-1-driven c-myc transcription, and (2) an alternative pathway exists for TGF-beta1-mediated growth inhibition of v-Abl-transformed cells, in which increased rather than decreased E2F-mediated c-myc transcription is observed.


Assuntos
Proteínas de Transporte , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , DNA/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína do Retinoblastoma/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Animais , Linhagem Celular Transformada , Fatores de Transcrição E2F , Fator de Transcrição E2F1 , Camundongos , Proteínas Recombinantes de Fusão/metabolismo , Proteína do Retinoblastoma/genética , Proteína 1 de Ligação ao Retinoblastoma , Fator de Transcrição DP1 , Fatores de Transcrição/genética , Transcrição Gênica , Transfecção
4.
Mol Cell Biol ; 15(11): 6088-99, 1995 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-7565761

RESUMO

Deregulated expression of v-abl and BCR/abl genes has been associated with myeloproliferative syndromes and myelodysplasia, both of which can progress to acute leukemia. These studies identify the localization of the oncogenic form of the abl gene product encoded by the Abelson murine leukemia virus in the nuclei of myeloid cells and the association of the v-Abl protein with the transcriptional regulator cyclic AMP response element-binding protein (CREB). We have mapped the specific domains within each of the proteins responsible for this interaction. We have shown that complex formation is a prerequisite for transcriptional potentiation of CREB. Transient overexpression of the homologous cellular protein c-Abl also results in the activation of promoters containing an intact CRE. These observations identify a novel function for v-Abl, that of a transcriptional activator that physically interacts with a transcription factor.


Assuntos
Núcleo Celular/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Oncogênicas v-abl/metabolismo , Proteínas de Saccharomyces cerevisiae , Fatores de Transcrição , Ativação Transcricional , Sequência de Bases , Sítios de Ligação , Compartimento Celular , Transformação Celular Viral , Células Cultivadas , Citoplasma/metabolismo , Proteínas de Ligação a DNA , Proteínas Fúngicas/metabolismo , Humanos , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos/química , Ligação Proteica
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