Transcellular biosynthesis of cysteinyl leukotrienes in vivo during mouse peritoneal inflammation

Leukotrienes (LTs) are lipid mediators of inflammation formed by enzymatic oxidation of arachidonic acid. One intriguing aspect of LT production is transcellular biosynthesis: cells expressing 5-lipoxygenase (5LO) form LTA4 and transfer it to cells expressing LTA4 hydrolase (LTA4H) or LTC4 synthase (LTC4S) to produce LTB4 or LTC4. This process has been demonstrated in vivo for LTB4, but not for cysteinyl LTs (cysLTs). We examined transcellular cysLT synthesis during zymosan-induced peritonitis, using bone marrow transplants with transgenic mice deficient in key enzymes of LT synthesis and analyzing all eicosanoids by liquid chromatography/tandem mass spectrometry. WT mice time-dependently produced LTB4 and cysLTs (LTC4, LTD4, and LTE4). 5LO−/− mice were incapable of producing LTs. WT bone marrow cells restored this biosynthetic ability, but 5LO−/− bone marrow did not rescue LT synthesis in irradiated WT mice, demonstrating that bone marrow-derived cells are the ultimate source of all LTs in this model. Total levels of 5LO-derived products were comparable in LTA4H−/− and WT mice, but were reduced in LTC4S−/− animals. No differences in prostaglandin production were observed between these transgenic or chimeric mice. Bone marrow cells from LTA4H−/− or LTC4S−/− mice injected into 5LO−/− mice restored the ability to synthesize LTB4 and cysLTs, providing unequivocal evidence of efficient transcellular biosynthesis of cysLTs. These results highlight the potential relevance of transcellular exchange of LTA4 for the synthesis of LTs mediating biological activities during inflammatory events in vivo.