Regulation of 5-lipoxygenase metabolism in mononuclear phagocytes by CD4 T lymphocytes.

ABSTRACT

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.