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.

Regulation of Lysophosphatidic Acid Receptor Expression and Function in Human Synoviocytes: Implications for Rheumatoid Arthritis?

“…Other studies also illustrated that LPA-induced IL-8 and IL-6 secretion is regulated by p38 MAPK (Saatian et al, 2006), p42/44 MAPK, and Rho kinase (Oz-Arslan et al, 2006;Saatian et al, 2006). Here we show that LPA-induced FLS motility depends on the activation of p38 MAPK and Rho but not p42/44 MAPK or JNK.…”

Molecular characterization and expression profiles in response to bacterial infection of Chinese soft-shelled turtle interleukin-8 (IL-8), the first reptilian chemokine gene

“…In response to both endogenous (IL-1, TNF) and exogenous (LPS) stimuli, IL-8 can be produced by many cell types (including monocyte/macrophage, neutrophil, vascular endothelial cell, epithelial cell, fibroblast, mast cell, dendritic cell, T lymphocyte, etc.) and influences a variety of leukocyte functions [7][8][9]. It mainly attracts neutrophils and induces them to release lysozomal enzymes, undergo a change in shape, trigger the respiratory burst, and increase the expression of adhesion molecules on the cell surface (reviewed in Ref.…”

Effects of Lysophospholipids on Tumor Microenvironment

“…Moreover, ELISA experiments demonstrated that addition of LPA to immature DCs in the presence of LPS enhances the secretion of CXCL8/IL-8 and IL-6 [106]. Studies also showed that G i protein and MAPkinase pathways are involved in these cell responses.…”