Cytochrome P450 1A1 enhances Arginase-1 expression, which reduces LPS-induced mouse peritonitis by targeting JAK1/STAT6

Cell Immunol. 2020 Mar:349:104047. doi: 10.1016/j.cellimm.2020.104047. Epub 2020 Jan 25.

Abstract

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.

Keywords: Arginase-1; Cytochrome P450 1A1; Macrophage; Peritonitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / pharmacology
  • Adoptive Transfer
  • Animals
  • Arachidonate 15-Lipoxygenase / physiology
  • Arginase / biosynthesis*
  • Arginase / genetics
  • Cytochrome P-450 CYP1A1 / biosynthesis
  • Cytochrome P-450 CYP1A1 / genetics
  • Cytochrome P-450 CYP1A1 / physiology*
  • Endotoxins / toxicity
  • Humans
  • Hydroxyeicosatetraenoic Acids / biosynthesis
  • Hydroxyeicosatetraenoic Acids / genetics
  • Hydroxyeicosatetraenoic Acids / pharmacology
  • Interleukin-4 / pharmacology
  • Janus Kinase 1 / antagonists & inhibitors*
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / transplantation
  • Macrophages, Peritoneal / drug effects*
  • Macrophages, Peritoneal / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peritonitis / chemically induced
  • Peritonitis / prevention & control*
  • RAW 264.7 Cells
  • RNA Interference
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, Cytoplasmic and Nuclear / biosynthesis
  • Receptors, Cytoplasmic and Nuclear / genetics
  • STAT6 Transcription Factor / antagonists & inhibitors*
  • Signal Transduction / drug effects*
  • THP-1 Cells
  • Up-Regulation / drug effects

Substances

  • Endotoxins
  • Hydroxyeicosatetraenoic Acids
  • Nr5a2 protein, mouse
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Stat6 protein, mouse
  • Interleukin-4
  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
  • endotoxin, Escherichia coli
  • 15-hydroxy-5,8,11,13-eicosatetraenoic acid
  • Arachidonate 15-Lipoxygenase
  • CYP1A1 protein, human
  • Cyp1a1 protein, mouse
  • Cytochrome P-450 CYP1A1
  • JAK1 protein, human
  • Jak1 protein, mouse
  • Janus Kinase 1
  • Arg1 protein, mouse
  • Arginase