IL-6 and IL-8 release is mediated via multiple signaling pathways after stimulating dendritic cells with lysophospholipids

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...

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Published in:	Journal of leukocyte biology Vol. 80; no. 2; pp. 287 - 297
Main Authors:	Öz‐Arslan, Devrim, Rüscher, Wolfgang, Myrtek, Daniel, Ziemer, Mirjana, Jin, Yixin, Damaj, Bassam B., Sorichter, Stephan, Idzko, Marco, Norgauer, Johannes, Maghazachi, Azzam A.
Format:	Journal Article
Language:	English
Published:	United States Society for Leukocyte Biology 01-08-2006
Subjects:	Cells, Cultured Dendritic Cells - metabolism Dendritic Cells - physiology Dose-Response Relationship, Drug ERK GTP-Binding Proteins - physiology Humans Interleukin-6 - blood Interleukin-8 - blood LPA Lysophospholipids - pharmacology Mitogen-Activated Protein Kinase Kinases - physiology PLC PLD Protein Kinase C - physiology Receptor Cross-Talk Rho rho GTP-Binding Proteins - physiology S1P secretion Signal Transduction Sphingosine - analogs & derivatives Sphingosine - pharmacology Time Factors
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Summary:	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.
Bibliography:	These authors contributed equally to this work. azzam.maghazachi@medisin.uio.no Correspondence: Department of Physiology, University of Oslo, Oslo, Norway. E‐mail ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0741-5400 1938-3673
DOI:	10.1189/jlb.1205751