Soluble epoxide hydrolase maintains steady-state lipid turnover linked with autocrine signaling in peritoneal macrophages

Soluble epoxide hydrolase is a widely distributed bifunctional enzyme that contains N-terminal phosphatase (N-phos) and C-terminal epoxide hydrolase (C-EH) domains. C-EH hydrolyzes anti-inflammatory epoxy-fatty acids to corresponding diols and contributes to various inflammatory conditions. However, N-phos has been poorly examined. In peritoneal macrophages, the N-phos inhibitor amino-hydroxybenzoic acid (AHBA) seemed to primarily interrupt the dephosphorylation of lysophosphatidates and broadly attenuated inflammation-related functions. AHBA activated intrinsic lysophosphatidate and thromboxane A2 receptors by altering lipid-metabolite distribution; downstream the signaling, phospholipase C was facilitated to dampen intracellular Ca²⁺ stores and AKT kinase (protein kinase B) was activated to presumably inhibit inflammatory gene expression. Our data suggest that N-phos maintains steady-state phospholipid turnover connecting autocrine signaling and is a prospective target for controlling inflammatory responses in macrophages.