The Pseudomonas aeruginosa autoinducer N-3-oxododecanoyl homoserine lactone accelerates apoptosis in macrophages and neutrophils.
Quorum-sensing systems are critical regulators of the expression of virulence factors of various organisms, including Pseudomonas aeruginosa. Las and Rhl are two major quorum-sensing components, and they are regulated by their corresponding autoinducers, N-3-oxododecanoyl homoserine lactone (3-oxo-C(12)-HSL) and N-butyryl-L-homoserine lactone (C(4)-HSL). Recent progress has demonstrated the potential of quorum-sensing molecules, especially 3-oxo-C(12)-HSL, for modulation of the host immune system. Here we show the specific ability of 3-oxo-C(12)-HSL to induce apoptosis in certain types of cells. When bone marrow-derived macrophages were incubated with synthetic 3-oxo-C(12)-HSL, but when they were incubated not C(4)-HSL, significant loss of viability was observed in a concentration (12 to 50 micro M)- and incubation time (1 to 24 h)-dependent manner. The cytotoxic activity of 3-oxo-C(12)-HSL was also observed in neutrophils and monocytic cell lines U-937 and P388D1 but not in epithelial cell lines CCL-185 and HEp-2. Cells treated with 3-oxo-C(12)-HSL revealed morphological alterations indicative of apoptosis. Acceleration of apoptosis in 3-oxo-C(12)-HSL-treated cells was confirmed by multiple criteria (caspases 3 and 8, histone-associated DNA fragments, phosphatidylserine expression). Structure-activity correlation experiments demonstrated that the fine structure of 3-oxo-C(12)-HSL, the HSL backbone, and side chain length are required for maximal activity. These data suggest that Pseudomonas 3-oxo-C(12)-HSL specifically promotes induction of apoptosis, which may be associated with 3-oxo-C(12)-HSL-induced cytotoxicity in macrophages and neutrophils. Our data suggest that the quorum-sensing molecule 3-oxo-C(12)-HSL has critical roles in the pathogenesis of P. aeruginosa infection, not only in the induction of bacterial virulence factors but also in the modulation of host responses.
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis; D006714:Homoserine / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D011552:Pseudomonas Infections / Q000209:etiology; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity* / Q000502:physiology*; D020298:U937 Cells; D014774:Virulence
D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; C109860:N-(3-oxododecanoyl)homoserine lactone; D006714:Homoserine; D015107:4-Butyrolactone