RESUMO
During episodes of inflammation, neutrophils (polymorphonuclear leukocytes [PMNs]) encounter subendothelial matrix substrates that may require additional signaling pathways as directives for movement through the extracellular space. Using an in vitro endothelial and epithelial model, inhibitors of phosphoinositide 3-kinase (PI3K) were observed to promote chemoattractant-stimulated migration by as much as 8 +/- 0.3-fold. Subsequent studies indicated that PMNs respond in a similar manner to RGD-containing matrix substrates and that PMN-matrix interactions are potently inhibited by antibodies directed against beta(3)- but not beta(1)-integrin antibodies, and that PI3K inhibitors block beta(3)-integrin dependence. Biochemical analysis of intracellular beta(3)-integrin uncoupling by PI3K inhibitors revealed diminished beta(3)-integrin tyrosine phosphorylation and decreased association with p72(syk). Similarly, the p72(syk) inhibitor piceatannol promoted PMN transmatrix migration, whereas HIV-tat peptide-facilitated loading of peptides corresponding to the beta(3)-integrin cytoplasmic tail identified the functional tyrosine residues for this activity. These data indicate that PI3K-regulated beta(3)-integrin represents a natural "braking" mechanism for PMNs during transit through the extracellular matrix.
Assuntos
Antígenos CD/fisiologia , Quimiotaxia de Leucócito , Matriz Extracelular/fisiologia , Neutrófilos/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Glicoproteínas da Membrana de Plaquetas/fisiologia , Androstadienos/farmacologia , Anticorpos Monoclonais/farmacologia , Antígenos CD/química , Antígenos CD/imunologia , Linhagem Celular , Citoplasma/química , Endotélio Vascular/fisiologia , Inibidores Enzimáticos/farmacologia , Precursores Enzimáticos/antagonistas & inibidores , Precursores Enzimáticos/fisiologia , Epitélio/fisiologia , Humanos , Integrina beta3 , Peptídeos e Proteínas de Sinalização Intracelular , Leucotrieno B4/farmacologia , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Peroxidase/análise , Inibidores de Fosfoinositídeo-3 Quinase , Fosfotirosina/metabolismo , Glicoproteínas da Membrana de Plaquetas/química , Glicoproteínas da Membrana de Plaquetas/imunologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/fisiologia , Quinase Syk , WortmaninaRESUMO
The following article forms part of an overall submission which assisted the author in winning the 1996 Victorian Irving Buzzard Prize. It explores important present day issues of HIV and Breastfeeding and provides an overview of a developed Model designed to help the Midwife sensitively and informatively assist the HIV positive mother in all facets of her decision making regarding infant feeding, and many other associated issues.
