The Pseudomonas aeruginosa Quorum-Sensing Signal Molecule N -(3-Oxododecanoyl)- l -Homoserine Lactone Has Immunomodulatory Activity

Abstract

Diverse gram-negative bacterial cells communicate with each other by using diffusible N-acyl homoserine lactone (AHL) signal molecules to coordinate 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 bacteria, such as Pseudomonas aeruginosa, AHL-mediated quorum sensing is involved in the regulation of multiple virulence determinants. We therefore sought to determine whether the immune system is capable of responding to these bacterial signal molecules. Consequently the immunomodulatory properties of the AHLsN-(3-oxododecanoyl)-l-homoserine lactone (OdDHL) and N-(3-oxohexanoyl)-l-homoserine lactone (OHHL) were evaluated in murine and human leukocyte immunoassays in vitro. OdDHL, but not OHHL, inhibited lymphocyte proliferation and tumor necrosis factor alpha production by lipopolysaccharide-stimulated macrophages. Furthermore, OdDHL simultaneously and potently down-regulated the production of IL-12, a Th-1-supportive cytokine. At high concentrations (>7 × 10−5 M) OdDHL inhibited antibody production by keyhole limpet hemocyanin-stimulated spleen cells, but at lower concentrations (<7 × 10−5 M), antibody production was stimulated, apparently by increasing the proportion of the immunoglobulin G1 (IgG1) isotype. OdDHL also promoted IgE production by interleukin-4-stimulated human peripheral blood mononuclear cells. These data indicate that OdDHL may influence the Th-1–Th-2 balance in the infected host and suggest that, in addition to regulating the expression of virulence determinants, OdDHL may contribute to the pathogenesis of P. aeruginosa infections by functioning as a virulence determinant per se.

Quorum sensing: the many languages of bacteria

“…There are also a growing number of reports indicating that bacterial AHLs modulate gene expression of mammalian organisms. Most of these studies implicate the 3OC12-HSL of P. aeruginosa as influencing the production of several cytokines by immune cells 'in vitro' and 'in vivo' (Telford, 1998;Smith et al, 2001Smith et al, , 2002aRitchie et al, 2003;Tateda, 2003). However, some of these reports appear to be contradictory with respect to whether this crosskingdom signaling is beneficial or detrimental to the host.…”

Pseudomonas aeruginosa quorum sensing molecule N‐(3 oxododecanoyl)‐l‐homoserine lactone disrupts epithelial barrier integrity of Caco‐2 cells

“…Thus, a significant number of recent studies have evaluated the use of autoinducers for communication between bacteria, but the interactions of these signal molecules with host cells have been studied less extensively [10][11][12][13].…”

Quorum sensing and swarming migration in bacteria

“…Besides the immunomodulatory activity of the P. aeruginosa 3O,C 12 -HSL in immuno-compromised individuals [36,37], another eukaryotic response to bacterial AHLs was recently reported. The legume plant, Medicago truncatula, is able to detect bacterial AHLs from both symbiotic and pathogenic bacteria [38].…”