THE PSEUDOMONAS-AERUGINOSA QUORUM-SENSING SIGNAL MOLECULE N-(3-OXODODECANOYL)-1-HOMOSERINE LACTONE HAS IMMUNOMODULATORY ACTIVITY

Diverse gram-negative bacterial cells communicate with each other by u sing diffusible N-acyl homoserine lactone (AHL) signal molecules to co ordinate gene expression with cell population density. Accumulation of AHLs above a threshold concentration renders the population ''quorate ,'' and the appropriate target gene is activated. In pathogenic bacter ia, such as Pseudomonas aeruginosa, AHL-mediated quorum sensing is inv olved in the regulation of multiple virulence determinants, We therefo re sought to determine whether the immune system is capable of respond ing to these bacterial signal molecules, Consequently the immunomodula tory properties of the AHLs N-(3-oxododecanoyl)-L-homoserine lactone ( OdDHL) and N-(3-oxohexanoyl)-L-homoserine lactone (OHHL) were evaluate d in murine and human leukocyte immunoassays in vitro. OdDHL, but not OHHL, inhibited lymphocyte proliferation and tumor necrosis factor alp ha production by lipopolysaccharide-stimulated macrophages. Furthermor e, OdDHL simultaneously and potently down-regulated the production of IL-12, a Th-1-supportive cytokine. At high concentrations (>7 x 10(-5) M) OdDHL inhibited antibody production by keyhole limpet hemocyanin-s timulated spleen cells, but at lower concentrations (<7 x 10(-5) M), a ntibody production was stimulated, apparently by increasing the propor tion of the immunoglobulin G1 (IgG1) isotype, OdDHL also promoted IgE production by interleukin-4-stimulated human peripheral blood mononucl ear cells, These data indicate that OdDHL mag influence the Th-1-Th-2 balance in the infected host and suggest that, in addition to regulati ng the expression of virulence determinants, OdDHL may contribute to t he pathogenesis of P. aeruginosa infections by functioning as a virule nce determinant per se.