Priming of human monocytes with leukotriene B4 enhances their sensitivity in IL-2-driven tumor necrosis factor-alpha production. Transcriptional and post-transcriptional up-regulation of IL-2 receptors.
Cytotoxic activity of monocytes may be mediated by their production of TNF-alpha, and IL-2 has been shown to induce TNF-alpha production in monocytes and alveolar macrophages. Unstimulated human monocytes constitutively express the beta-chain of the IL-2R (IL-2R beta), but little or no IL-2R alpha. When monocytes were pretreated with leukotriene (LT) B4, they responded to IL-2 with both enhanced production of TNF-alpha (two- to threefold) and, more strikingly, with augmented sensitivity (1000-fold) to IL-2. Treatment of monocytes with LTB4 induced IL-2R alpha gene transcription at 30 min and augmented expression of IL-2R alpha gene transcripts by 3 h, maximal at 10(-8) M LTB4. LTB4 induced increased shedding of the IL-2R alpha in the culture supernatants and a modest induction of IL-2R alpha protein expression on monocytes. On the other hand, although LTB4 could stimulate the cell membrane expression of IL-2R beta and the accumulation of IL-2R beta mRNA, LTB4 did not significantly affect IL-2R beta gene transcription. The augmented expression of IL-2R on monocytes was associated with augmented binding of 125I-labeled IL-2 to LTB4-pretreated monocytes. Our data present direct evidence that the inflammatory lipid mediator LTB4 can induce the expression of IL-2R alpha in human monocytes by activating IL-2R alpha gene transcription; it can also stimulate the expression of IL-2R beta, through post-transcriptional regulation; this augmented expression of both alpha- and beta-chains of the IL-2R is associated with enhanced sensitivity of monocytes to IL-2 in terms of TNF-alpha production and may be relevant to the proinflammatory actions of LTB4.
Stanková
J
J
Department of Pediatrics, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.
Dupuis
G
G
Gagnon
N
N
Thivierge
M
M
Turcotte
S
S
Rola-Pleszczynski
M
M
D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000032:analysis / Q000235:genetics*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015854:Up-Regulation
D007376:Interleukin-2; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4