13-hydroxy-9-11-octadecadienoic-acid and lysophosphatidic-acid

Peripheral sensitization during inflammatory pain is mediated by a variety of endogenous proalgesic mediators including a number of oxidized lipids, some of which serve endogenous modulators of sensory TRP-channels. These lipids are eicosanoids of the arachidonic acid and linoleic acid pathway, as well as lysophophatidic acids (LPAs). However, their regulation pattern during inflammatory pain and their contribution to peripheral sensitization is still unclear. Here, we used the UVB-model for inflammatory pain to investigate alterations of lipid concentrations at the site of inflammation, the dorsal root ganglia (DRGs) as well as the spinal dorsal horn and quantified 21 lipid species from five different lipid families at the peak of inflammation 48 hours post irradiation. We found that known proinflammatory lipids as well as lipids with unknown roles in inflammatory pain to be strongly increased in the skin, whereas surprisingly little changes of lipid levels were seen in DRGs or the dorsal horn. Importantly, although there are profound differences between the number of cytochrome (CYP) genes between mice and rats, CYP-derived lipids were regulated similarly in both species. Since TRPV1 agonists such as LPA 18∶1, 9- and 13-HODE, 5- and 12-HETE were elevated in the skin, they may contribute to thermal hyperalgesia and mechanical allodynia during UVB-induced inflammatory pain. These results may explain why some studies show relatively weak analgesic effects of cyclooxygenase inhibitors in UVB-induced skin inflammation, as they do not inhibit synthesis of other proalgesic lipids such as LPA 18∶1, 9-and 13-HODE and HETEs.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonic Acid; Eicosanoids; Ganglia, Spinal; Hydroxyeicosatetraenoic Acids; Hyperalgesia; Linoleic Acid; Linoleic Acids; Lysophospholipids; Mice; Rats; TRPV Cation Channels; Ultraviolet Rays

We analyzed global gene expression profiles of IL-4 induced alternatively activated as well as IFNγ+TNFα stimulated classically activated human monocyte derived macrophages and identified novel IL-4 regulated alternative activation marker genes including MS4A4A, SLA, CD180, and ENPP2. Transcription factor prediction analysis of IL-4 regulated genes suggested that the regulated genes are involved in a complex regulation of lipid metabolism, defense against cell metabolism derived reactive oxygen species, and basal expression of inflammation linked genes. Both an in silico transcription activation prediction as well as experimental data suggested the presence of alternative macrophage activation specific endogenous PPARγ ligand producing mechanisms. We found the induction of three enzymes whose activity can potentially generate endogenous PPARγ ligands in an IL-4 dependent manner. These are MAOA, ENPP2, and ALOX15 producing 5-methoxy-indole acetate, lysophosphatidic acid (LPA) and 13-hydroxyoctadienoic acid (13-HODE), and/or 15-hydroxyeicosatetraenoic acid (15-HETE), respectively. Our data suggest that global gene expression profiling, combined with computational transcription activity prediction, can lead to identification of transcriptional networks that underpin cellular subtype specification.

Topics: Adaptor Proteins, Signal Transducing; Antigens, CD; Arachidonate 15-Lipoxygenase; Biomarkers; Cell Differentiation; Cells, Cultured; Gene Expression; Gene Expression Profiling; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Interferon-gamma; Interleukin-4; Ligands; Linoleic Acids; Lipid Metabolism; Lysophospholipids; Macrophage Activation; Macrophages; Membrane Proteins; Monoamine Oxidase; Phosphoric Diester Hydrolases; PPAR gamma; Proto-Oncogene Proteins pp60(c-src); Reactive Oxygen Species; Transcription Factors; Transcriptional Activation; Tumor Necrosis Factor-alpha