Pseudomonas aeruginosa has two well-characterized quorum-sensing systems, Las and Rhl. These systems are composed of LuxR-type
proteins, LasR and RhlR, and two
acyl homoserine lactone (AHL) synthases, LasI and RhlI. LasI catalyzes the synthesis of
N-(3-oxododecanoyl)homoserine lactone (3O-C12-HSL), whereas RhlI catalyzes the synthesis of N-butyryl-
homoserine lactone. There is little known about the importance of AHLs in vivo and what effects these molecules have on eukaryotic cells. In order to understand the role of AHLs in vivo, we first tested the effects that deletions of the synthase genes in P. aeruginosa had on colonization of the lung. We demonstrate that in an adult mouse acute-
pneumonia model, deletion of the lasI gene or both the lasI and rhlI genes greatly diminished the ability of P. aeruginosa to colonize the lung. To determine whether AHLs have a direct effect on the host, we examined the effects of
3O-C12-HSL injected into the skin of mice. In this model, 3O-C(12)-HSL stimulated a significant induction of mRNAs for the
cytokines interleukin-1alpha (IL-1alpha) and
IL-6 and the
chemokines macrophage inflammatory protein 2 (MIP-2),
monocyte chemotactic protein 1,
MIP-1beta, inducible
protein 10, and T-cell activation gene 3. Additionally, dermal
injections of
3O-C12-HSL also induced
cyclooxygenase 2 (Cox-2) expression. The Cox-2
enzyme is important for the conversion of
arachidonic acid to
prostaglandins and is associated with
edema, inflammatory infiltrate,
fever, and
pain. We also demonstrate that
3O-C12-HSL activates T cells to produce the inflammatory
cytokine gamma interferon and therefore potentially promotes a Th1 environment. Induction of these inflammatory mediators in vivo is potentially responsible for the significant influx of white blood cells and subsequent tissue destruction associated with
3O-C12-HSL dermal
injections. Therefore, the quorum-sensing systems of P. aeruginosa contribute to its pathogenesis both by regulating expression of
virulence factors (exoenzymes and toxins) and by inducing
inflammation.