Mouse peritoneal macrophages contain abundant omega-6 lipoxygenase activity that is independent of interleukin-4.
The action of an omega-6 lipoxygenase (LO) has been implicated in the development of atherosclerosis through a mechanism involving oxidation of LDL, and its regulation in macrophages may have important implications for the disease process. Human monocyte-derived macrophages (HMDMs) showed no demonstrable LO protein or activity unless they were incubated with interleukin-4 (IL-4). In contrast, mouse peritoneal macrophages (MPMs) possessed significant basal levels of LO activity and protein that were augmented by IL-4 treatment. Interferon gamma prevented the induction of LO in both HMDMs and MPMs. Whereas interferon gamma could completely block the IL-4 induction of LO in human cells, it did not suppress basal LO activity in MPMs. Both HMDMs and MPMs exhibited similar concentration-response relationships for stimulation of LO activity and protein, with maximal induction at 1 ng/mL IL-4. The time course of IL-4 induction of LO activity was markedly different in human and murine cells. IL-4 induced LO activity and protein in human cells by 48 hours that were maximal by 72 hours; there was a decline to a new baseline by 96 hours. MPMs have a significant amount of LO activity at baseline, which declined with time by nearly 10-fold in the absence of IL-4, IL-4 blunted the decline of LO activity with time and restored activity to that found at baseline by 48 hours. IL-4 was not responsible for the LO activity present in freshly isolated MPMs since both activity and protein content were similar in cells harvested from IL-4+/+ and IL-/- mice. Therefore, whereas IL-4 may be an important modulator of LO production in vitro, it is not essential for the in vivo expression of this protein. Further, these studies demonstrate that significant differences exist between monocyte-derived macrophages matured in vitro and tissue macrophages that have matured in vivo.
Cornicelli
J A
JA
Department of Atherosclerosis Therapeutics, Parke-Davis Pharmaceutical Research Division, Warner Lambert Co, Ann Arbor, MI, USA. cornicj@aa.wl.com
Welch
K
K
Auerbach
B
B
Feinmark
S J
SJ
Daugherty
A
A
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D008084:Lipoxygenase / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000201:enzymology*; D051379:Mice
D015847:Interleukin-4; D008084:Lipoxygenase