title: IL-6 and IL-8 release is mediated via multiple signaling pathways after stimulating dendritic cells with lysophospholipids.
abstract: Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are bioactive lipid mediators, which are known to play major roles in allergic reactions as well as in tumor pathogenesis. Here, the biological activities and signal pathways of these lysophospholipids (LPLs) in dendritic cells (DCs) were characterized further. Flow cytometric and immunoblot analyses indicate that immature as well as mature DCs express the LPL receptors S1P1, S1P3, S1P5, and LPA2, but not S1P2, S1P4, LPA1, or LPA3. Moreover, enzyme-linked immunosorbent assay experiments demonstrate that simultaneous addition of these LPLs to immature DCs in the presence of lipopolysaccharide enhanced the secretion of the inflammatory cytokines interleukin (IL)-6 and IL-8 in maturing DCs. In contrast, no modification of IL-6 or IL-8 release was observed after exposure of mature DCs to LPLs alone. In addition, studies with pertussis toxin and mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059 suggested that Gi proteins and MAPK pathway are involved in these LPL-induced cell responses. Corroborating these findings, we observed that LPLs induce the phosphorylation of extracellular signal-regulated kinase 1/2 in immature DCs but not in mature DCs. Further analyses show that inhibitors of phosholipase D, Rho, and protein kinase C also inhibited the LPL-induced release of IL-6 and IL-8. Therefore, our findings suggest that lipopolysaccharide in DCs uncouples LPL receptors from the signal-transducing machinery during maturation and that exposure of LPLs at early time-points to maturing DCs modifies the proinflammatory capacity of mature DCs.
authors.affiliation: Department of Anatomy, University of Oslo, Norway.
authors.forename: Devrim
authors.initials: D
authors.lastname: Oz-Arslan
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rüscher
authors.forename: Daniel
authors.initials: D
authors.lastname: Myrtek
authors.forename: Mirjana
authors.initials: M
authors.lastname: Ziemer
authors.forename: Yixin
authors.initials: Y
authors.lastname: Jin
authors.forename: Bassam B
authors.initials: BB
authors.lastname: Damaj
authors.forename: Stephan
authors.initials: S
authors.lastname: Sorichter
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.forename: Johannes
authors.initials: J
authors.lastname: Norgauer
authors.forename: Azzam A
authors.initials: AA
authors.lastname: Maghazachi
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D016209:Interleukin-8 / Q000097:blood*; D008246:Lysophospholipids / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D020741:rho GTP-Binding Proteins / Q000502:physiology
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D013110:Sphingosine