Regulation of 5-lipoxygenase metabolism in mononuclear phagocytes by CD4 T lymphocytes.
Alveolar macrophages (AM) are the primary resident effector cells in the alveolus. Leukotrienes (LT) are secreted by AM in their role as defender of the lung. 5-Lipoxygenase (5-LO) catalyzes the synthesis of LT in association with 5-LO-activating protein, termed "FLAP." AM demonstrate increased 5-LO metabolism compared to peripheral blood monocytes (PBM). Activated lymphocytes release mediators which upregulate 5-LO metabolism in PBM. The lymphocyte population of the lung consists predominantly of CD4+ helper constitutively "activated" T cells. We hypothesized that mediators released by pulmonary CD4+ T cells may upregulate and maintain of 5-LO metabolism in PBM as they enter the alveolar space and differentiate into AM. 5-LO metabolism in AM from CD4-depleted mice demonstrated reduced LT synthesis (LTC4: 66.9 +/- 8%; LTB4 61.4 +/- 6.2% control). The decrease in 5-LO metabolism was associated with reduced FLAP (30.1 +/- 14.5% of control) and 5-LO expression (49 +/- 13.7% of control). This defect in AM 5-LO metabolism in CD4-depleted mice was further associated with reduced LTC4 levels in bronchoalveolar lavage (BAL) fluid. In summary, factors secreted constitutively by lung lymphocytes, in particular CD4 cells, contribute to the increased 5-LO metabolism in AM.
Coffey
M J
MJ
Division of Pulmonary, University of Michigan Medical Center, Ann Arbor 48109-0642, USA. mcoffey@umich.edu
Phare
S M
SM
Peters-Golden
M
M
Huffnagle
G B
GB
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D002450:Cell Communication; D007975:Leukotriene B4 / Q000096:biosynthesis; D017997:Leukotriene C4 / Q000096:biosynthesis; D008212:Lymphocyte Depletion; D016676:Macrophages, Alveolar / Q000201:enzymology* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D010586:Phagocytes / Q000201:enzymology* / Q000378:metabolism
D058927:5-Lipoxygenase-Activating Proteins; C548593:Alox5ap protein, mouse; D002352:Carrier Proteins; D008565:Membrane Proteins; D007975:Leukotriene B4; D016718:Arachidonic Acid; D017997:Leukotriene C4; D001094:Arachidonate 5-Lipoxygenase