title: N-(3-oxo-acyl)homoserine lactones signal cell activation through a mechanism distinct from the canonical pathogen-associated molecular pattern recognition receptor pathways.
abstract: Innate immune system receptors function as sensors of infection and trigger the immune responses through ligand-specific signaling pathways. These ligands are pathogen-associated products, such as components of bacterial walls and viral nuclear acids. A common response to such ligands is the activation of mitogen-activated protein kinase p38, whereas double-stranded viral RNA additionally induces the phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha). Here we have shown that p38 and eIF2alpha phosphorylation represent two biochemical markers of the effects induced by N-(3-oxo-acyl)homoserine lactones, the secreted products of a number of Gram-negative bacteria, including the human opportunistic pathogen Pseudomonas aeruginosa. Furthermore, N-(3-oxo-dodecanoyl)homoserine lactone induced distension of mitochondria and the endoplasmic reticulum as well as c-jun gene transcription. These effects occurred in a wide variety of cell types including alveolar macrophages and bronchial epithelial cells, requiring the structural integrity of the lactone ring motif and its natural stereochemistry. These findings suggest that N-(3-oxo-acyl)homoserine lactones might be recognized by receptors of the innate immune system. However, we provide evidence that N-(3-oxo-dodecanoyl)homoserine lactone-mediated signaling does not require the presence of the canonical innate immune system receptors, Toll-like receptors, or two members of the NLR/Nod/Caterpillar family, Nod1 and Nod2. These data offer a new understanding of the effects of N-(3-oxo-dodecanoyl)homoserine lactone on host cells and its role in persistent airway infections caused by P. aeruginosa.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kravchenko
authors.forename: Gunnar F
authors.initials: GF
authors.lastname: Kaufmann
authors.forename: John C
authors.initials: JC
authors.lastname: Mathison
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.forename: Alexander Z
authors.initials: AZ
authors.lastname: Katz
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Wood
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Brogan
authors.forename: Mandy
authors.initials: M
authors.lastname: Lehmann
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Mee
authors.forename: Kazunori
authors.initials: K
authors.lastname: Iwata
authors.forename: Qilin
authors.initials: Q
authors.lastname: Pan
authors.forename: Colleen
authors.initials: C
authors.lastname: Fearns
authors.forename: Ulla G
authors.initials: UG
authors.lastname: Knaus
authors.forename: Michael M
authors.initials: MM
authors.lastname: Meijler
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ulevitch
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000502:physiology; D020816:Amino Acid Motifs; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000382:microbiology*; D005786:Gene Expression Regulation; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011550:Pseudomonas aeruginosa / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D012367:RNA, Viral; C088386:homoserine lactone; D015107:4-Butyrolactone