Role of leukotriene B₄ in the interleukin‐4‐induced human mononuclear phagocyte activation

Abstract

SUMMARYInterleukin-4 (IL-4) induced a time-and dose-dependent production of leukotriene B 4 (LTB 4 ) by human resting monocytes indicating that IL-4 induced the activation of the 5-lipoxygenase pathway in resting human monocytes. Maximal effect was observed in the presence of 10 ng/ml IL-4, and in kinetics experiments LTB 4 production plateaued 40 min after the onset of stimulation. When stimulated for 48 hr with IL-4, resting human monocytes expressed and released the low-affinity receptor for IgE (CD23) and were partially inhibited in the presence of a highly non-redox 5-lipoxygenase inhibitor (BW B70C), suggesting that the production of LTB 4 partially contributed to the IL-4-induced CD23 expression and release. This hypothesis was strengthened by the fact that exogenous LTB 4 (10 nM) was found to increase the effect of a suboptimal dose of IL-4 (1 ng/ml). In addition to these phenotypical changes, IL-4 primed the phorbol-12-myristate-13-acetate (PMA)-induced luminol-dependent chemiluminescence response (LDCL) by normal human monocytes, this priming effect being abrogated in the presence of BW B70C. Taken together, these data indicated that IL-4 induced the production of LTB 4 by activation of the 5-lipoxygenase pathway in human monocytes, and that the activation of this pathway could upregulate the expression and release of CD23 and the respiratory burst of these cells.

<i>FADS</i> Gene Cluster Polymorphisms: Important Modulators of Fatty Acid Levels and Their Impact on Atopic Diseases

“…This defect in enzyme activity would explain the proposed dysregulation of arachidonic acid metabolism in atopy [50] . Arachidonic acid is one of the main precursors of prostaglandins and leukotrienes [51] and activates allergic immune responses via its products, prostaglandin E2 and leukotriene B4 [52][53][54][55][56] . For -3 fatty acids like eicosapentaenoic acid and docosahexaenoic acid, modulation of cytokine responses has also been shown [57] , whereas dietary treatment with these -3 fatty acids in inflammatory disorders suggests rather anti-inflammatory properties in contrast to the products of arachidonic acid [58] .…”

Polyunsaturated n−3 fatty acids and the development of atopic disease

“…See Table 1 PUFA levels in cord serum phospholipids and atopy during childhood (24,28,31) raise the question of whether such a dysfunction is primary or secondary to a sustained allergic inflammation. The important role of AA in PGE 2 and LTB 4 metabolism and the relation to allergic inflammation (10)(11)(12)(13)(14) have led to the hypothesis that there is a dysregulation of AA metabolism in atopy (37). For example, a higher production of PGE 2 has been shown in monocytes from atopic individuals (38,39).…”

“…Furthermore, enhanced PGE 2 production in antigen-presenting cells (APC) commits naive T helper (Th) cells toward a Th2-like cytokine pattern favoring IgE production (12,13). Furthermore, IL-4 induces CD23 membrane expression in monocytes, partly through the induction of LTB 4 synthesis (14). The IL-4-induced IgE production in humans can be further stimulated by LTB 4 , through an increase of IL-4R positive cells and release of sCD23 from mononuclear cells.…”

Expression of 5‐lipoxygenase (5‐LOX) in T lymphocytes

“…For example, LTB 4 is a powerful chemoattractant agent for inflammatory cells and induces degranulation, superoxide anion production and adherence of neutrophils to vascular endothelial cells. LTB 4 also stimulates the production of proinflammatory cytokines, including interleukin‐1β (IL‐1β), 10,11 IL‐2, 12,13 IL‐6 14 and interferon‐γ (IFN‐γ), 15 anti‐inflammatory cytokines, such as IL‐4 16 and IL‐10, 17 and activates c‐fos , c‐jun 18 and nuclear factor‐κB gene transcription 10 . It also increases the expression of the IL‐2 receptor β‐chain in natural killer cells and to a lesser extent in CD8 + lymphocytes, resulting in a cytotoxic response 19 .…”