15-hydroxy-5-8-11-13-eicosatetraenoic-acid and Peritonitis

The polarization of macrophages is critical to inflammation and tissue repair, with unbalanced macrophage polarization associated with critical dysfunctions of the immune system. Cytochrome P450 1A1 (CYP1A1) is a hydroxylase mainly controlled by the inflammation-limiting aryl hydrocarbon receptor (AhR), which plays a critical role in mycoplasma infection, oxidative stress injury, and cancer. Arginase-1 (Arg-1) is a surrogate for polarized alternative macrophages and is important to the production of nitric oxide (NO) by the modulation of arginine. In the present study, we found CYP1A1 to be upregulated in IL-4-stimulated mouse peritoneal macrophages (PMs) and human peripheral blood monocytes. Using CYP1A1-overexpressing RAW264.7 cells (CYP1A1/RAW) we found that CYP1A1 augmented Arg-1 expression by strengthening the activation of the JAK1/STAT6 signaling pathway in macrophages treated with IL-4. 15(S)-HETE, a metabolite of CYP1A1 hydroxylase, was elevated in IL-4-induced CYP1A1/RAW cells. Further, in macrophages, the loss-of-CYP1A1-hydroxylase activity was associated with reduced IL-4-induced Arg-1 expression due to impaired 15(S)-HETE generation. Of importance, CYP1A1 overexpressing macrophages reduced the inflammation associated with LPS-induced peritonitis. Taken together, these findings identified a novel signaling axis, CYP1A1-15(S)-HETE-JAK1-STAT6, that may be a promising target for the proper maintenance of macrophage polarization and may also be a means by which to treat immune-related disease due to macrophage dysfunction.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adoptive Transfer; Animals; Arachidonate 15-Lipoxygenase; Arginase; Cytochrome P-450 CYP1A1; Endotoxins; Humans; Hydroxyeicosatetraenoic Acids; Interleukin-4; Janus Kinase 1; Leukocytes, Mononuclear; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Peritonitis; RAW 264.7 Cells; Receptors, Cytoplasmic and Nuclear; RNA Interference; RNA, Messenger; Signal Transduction; STAT6 Transcription Factor; THP-1 Cells; Up-Regulation

Ten frogs (Xenopus laevis) were injected with mixed bacteria to produce a septic peritonitis. Peritoneal inflammatory cells of eight animals were studied for monohydroxyeicosanoid and leukotriene production from exogenous arachidonic acid. Large amounts of 12-hydroxyeicosatetraenoic acid were produced; smaller amounts of 5- and 15-hydroxyeicosatetraenoic and leukotriene B4 were produced. Identifications were confirmed by retention times on HPLC, ultraviolet spectroscopy on all products, and gas chromatograph/mass spectrometry in the case of 12-hydroxyeicosatetraenoic acid.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Chromatography, High Pressure Liquid; Female; Gas Chromatography-Mass Spectrometry; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Male; Peritoneal Cavity; Peritonitis; Xenopus laevis