RESUMO
Using a mouse mutagenesis screen, we have identified CD83 as being critical for the development of CD4(+) T cells and for their function postactivation. CD11c(+) dendritic cells develop and function normally in mice with a mutated CD83 gene but CD4(+) T cell development is substantially reduced. Additionally, we now show that those CD4(+) cells that develop in a CD83 mutant animal fail to respond normally following allogeneic stimulation. This is at least in part due to an altered cytokine expression pattern characterized by an increased production of IL-4 and IL-10 and diminished IL-2 production. Thus, in addition to its role in selection of CD4(+) T cells, absence of CD83 results in the generation of cells with an altered activation and cytokine profile.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Imunoglobulinas/genética , Glicoproteínas de Membrana/genética , Sequência de Aminoácidos , Animais , Antígenos CD , Sequência de Bases , Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Células Dendríticas/imunologia , Feminino , Imunoglobulinas/imunologia , Masculino , Glicoproteínas de Membrana/imunologia , Camundongos , Dados de Sequência Molecular , Mutação , Linhagem , Antígeno CD83RESUMO
We describe the development of statine-based peptidomimetic inhibitors of human beta-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions: an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Abeta secretion in human embryonic kidney cells.
Assuntos
Aminoácidos/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Oligopeptídeos/química , Aminoácidos/química , Aminoácidos/farmacologia , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Linhagem Celular , Endopeptidases , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Mimetismo Molecular , Relação Estrutura-AtividadeRESUMO
By use of the effectively cleaved beta-secretase (BACE) substrate (1), incorporation of a statine in P(1) resulted in a weak inhibitor 13 of the enzyme. Further substitution of P(1)'-Asp by P(1)'-Val in 13 results in a potent inhibitor 22 of BACE. Removal of the P(10)-P(5) residues on the N-terminal part of inhibitor 22 resulted in no loss of potency (23). C-terminal truncations of inhibitor 22 generally led to significant loss of potency.
