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1.
J Biol Chem ; 288(8): 5718-31, 2013 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-23275335

RESUMO

Class IA phosphoinositide 3-kinase (PI3K) is essential for clonal expansion, differentiation, and effector function of B and T lymphocytes. The p110δ catalytic isoform of PI3K is highly expressed in lymphocytes and plays a prominent role in B and T cell responses. Another class IA PI3K catalytic isoform, p110α, is a promising drug target in cancer but little is known about its function in lymphocytes. Here we used highly selective inhibitors to probe the function of p110α in lymphocyte responses in vitro and in vivo. p110α inhibition partially reduced B cell receptor (BCR)-dependent AKT activation and proliferation, and diminished survival supported by the cytokines BAFF and IL-4. Selective p110δ inhibition suppressed B cell responses much more strongly, yet maximal suppression was achieved by targeting multiple PI3K isoforms. In mouse and human T cells, inhibition of single class IA isoforms had little effect on proliferation, whereas pan-class I inhibition did suppress T cell expansion. In mice, selective p110α inhibition using the investigational agent MLN1117 (previously known as INK1117) did not disrupt the marginal zone B cell compartment and did not block T cell-dependent germinal center formation. In contrast, the selective p110δ inhibitor IC87114 strongly suppressed germinal center formation and reduced marginal zone B cell numbers, similar to a pan-class I inhibitor. These findings show that although acute p110α inhibition partially diminishes AKT activation, selective p110α inhibitors are likely to be less immunosuppressive in vivo compared with p110δ or pan-class I inhibitors.


Assuntos
Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica , Linfócitos/citologia , Inibidores de Fosfoinositídeo-3 Quinase , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Imunossupressores/farmacologia , Linfócitos/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Isoformas de Proteínas , Transdução de Sinais , Baço/citologia , Linfócitos T/citologia , Linfócitos T/enzimologia
2.
Gene ; 512(2): 211-8, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23107765

RESUMO

The specific role of endogenous Bmp2 gene in chondrocytes and in osteoblasts in fracture healing was investigated by generation and analysis of chondrocyte- and osteoblast-specific Bmp2 conditional knockout (cKO) mice. The unilateral open transverse tibial fractures were created in these Bmp2 cKO mice. Bone fracture callus samples were collected and analyzed by X-ray, micro-CT, histology analyses, biomechanical testing and gene expression assays. The results demonstrated that the lack of Bmp2 expression in chondrocytes leads to a prolonged cartilage callus formation and a delayed osteogenesis initiation and progression into mineralization phase with lower biomechanical properties. In contrast, when the Bmp2 gene was deleted in osteoblasts, the mice showed no significant difference in the fracture healing process compared to control mice. These findings suggest that endogenous BMP2 expression in chondrocytes may play an essential role in cartilage callus maturation at an early stage of fracture healing. Our studies may provide important information for clinical application of BMP2.


Assuntos
Proteína Morfogenética Óssea 2/biossíntese , Calo Ósseo/metabolismo , Condrócitos/metabolismo , Consolidação da Fratura/fisiologia , Fraturas Ósseas/metabolismo , Regulação da Expressão Gênica , Animais , Proteína Morfogenética Óssea 2/genética , Calo Ósseo/patologia , Calcificação Fisiológica/fisiologia , Condrócitos/patologia , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/genética , Fraturas Ósseas/patologia , Camundongos , Camundongos Knockout , Microtomografia por Raio-X
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