Regulation of tumor necrosis alpha converting enzyme (TACE) activity in immune cells by Staphylococcus aureus protein A

GIAI CONSTANZA; GAROFALO AILIN; SORDELLI DANIEL; GOMEZ MARISA

capital federal

Congreso; Congreso fraco -argentina-FAIC-LVIII Reunión Anual de la Sociedad Argentina de InmunologíaXIII Jornada Científica del Grupo Rioplatense de Citometría de Flujo 3º Jornadas Argentinas de Inmunodeficiencias Primarias (SAP); 2010

Sociedad Argentina de Inmunologia

S. aureus is a major human pathogen associated to diverse types of local and systemic infections with high morbidity and mortality. Among its many virulence factors, we have described the ability of protein A ( SpA) to mimic TNF- alpha responses by interacting with the type I TNF- alpha receptor (TNFR1) on airway epithelial cells. This interaction is critical for development of pneumonia. SpA also induces the cleavage of TNFR1 from the surface of epithelial cells, a process mediated by TACE. This metalloprotease plays a central role in immunity by regulating the release of pro- inflammatory cytokines and limiting inflammation through the shedding of citokine receptors. The aim of this study was to determine the role of SpA in the regulation of TACE activity in macrophages. We determined that purified SpA induces TNF- alpha production in macrophages. A decrease in TNF-alpha production was observed when the cells were stimulates with a spa null isogenic mutant as compared to wild type S. aureus. Both, the N-terminal and the C- terminal regions of SpA were involved in TNF- alpha secretion. S. aureus and SpA also rapidly induced shedding of TNFR1 and the type II IL-1 receptor (IL-1RII) in macrophages, a process that was mediated by the N- terminal region of SpA. Similar responses were observed in cells stimulated with Lactococcus lactis expresing SpA. Exposure of cells to SpA and L. lactis- SpA in the presence of TAPI-I, a biochemical inhibitor of TACE, resulted in a significantly dose- dependent inhibition of IL-1RII shedding (p