Human recombinant IL-1 receptor antagonist (IL-IRa) inhibits leukotriene B4 generation from human monocyte suspensions stimulated by lipopolysaccharide (LPS)

Abstract

SUMMARYThe efiect of human recombinant IL-1 receptor antagonist (hrlL-lRa) on leukotriene B4 (LTB4) release was investigated in activated human monocyte cultures. To stimulate LTB4 generation, LPS was used as an agonist. Detection was performed with the highly sensitive radioimmunoassay method. The cells were treated with scalar concentrations using LPS at I -IOOO ng/ml for different periods or lime. The greater LTB4 stimulaiion was found at LPS 100 ng/ml for 18 h incubation time. Preincubation of monocytes with cytochalasin B (CB) (5 ^ig/ml) for 15 min augmented the release of LTB4 when LPS was used. A dose-dependent inhibition was found when human monocytes were pretreated for 10 min with hrlL-l Ra at dilTerent concentrations (0-25-25O ng/ml) and then treated with LPS 100 ng/ml for 18 h. Maximum inhibition was observed at the highest concentration of hriLlRa (250 ng/ml), Macrophages treated with a non-selective 5-lipoxygenase inhibitor, nordihydroguaiarclic acid (NDGA). used at 10 fm, added 15 min before LPS 100 ng/ml. produee a dosedependent inhibition of LTB4, Cells pretreated with araehidonic acid, at various concentrations (U) " 10 'M)for 10 min and then treated with LPS 100 ng/ml for 18 h, were also inhibited in a dosedependent manner by hrlL-l Ra in their production of LTB4. The inhibition of LTB4 release by hriLIRa. in LPS-stimulatcd human monocytes. may suggest an important modulatory role for this new cytokine (monokine) in inflammation and immunity and may hold future therapeutic implications for disea.ses involving LTB4 as a mediator. [9][10][11][12]. in general the release ofeicosanoids is associated with many pathophysiological phenomena such as hypotension, thrombocytopenia. capillary leak syndrome. Icukopenia and fever, all factors involved in the shock syndrome which occurs, for example, in in viro cytokine therapies [13][14][15], Araehidonic acid. released from activated macrophages. is the precursor of eyelooxygenase and lipoxygenasc compounds. In particular. lunnan macrophages oxidatively metabolize endogenous ara-C'orrcspoiidoncc: Dr Pit* Conli. Immunology Divisitiii. Instilute of Experimental Medicine. University of Cliieti Medical School. Via dei Vestini. 66100 Chieti, Italy. chidonic add to teukotriene B4 {LTB4) (5S,I2R-dihydroxy-6. l4-cis-8. 10-trans eicosatetraenoic acid) by the specific lipoxygenation pathway. Macrophages cultured in vitro release LTB4 in response lo stimulation with LPS [I6|. Macrophages release an impressive array of biologically active molecules, among which are molecules with the ability to direct the stimulation of araehidonic acid products. LTB4 is one human macrophage product with numerous effects on a variety of leucocytes, which has a potent chemokinetic and chcmotaclic activity, induction of aggregation, and has a profound ability to modulate macrophage functions [16][17][18]. The receptor-stimulated activation mechanism is poorly understood. Following LPS stimulation of mononuclear phagocytes a number of events occur which are related to the release of LTB...

Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses

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Leukotriene B4 Augments and Restores FcγRs-dependent Phagocytosis in Macrophages

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Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review

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