Priming of alveolar macrophages by leukotriene D(4): potentiation of inflammation.
Cysteinyl leukotrienes (LTs), including LTC(4), LTD(4), and LTE(4), are well known to induce bronchoconstriction and increase bronchial hyperreactivity, mucus secretion, and vascular permeability. Interestingly, alveolar macrophages (AMs) express LTD(4) high-affinity receptor. These cells represent a major source of inflammatory mediators implicated in the pathophysiology of asthma. Thus, we investigated the immunomodulatory effects of LTD(4) on the production of inflammatory mediators such as macrophage inflammatory protein (MIP)- 1alpha, tumor necrosis factor (TNF), and nitric oxide (NO) by AMs. NR8383 cells, an AM cell line, were pretreated with LTD(4) (10(-11) M) for different periods of time and stimulated or not with lipopolysaccharide (LPS) for 2 h. Although LTD(4) treatment did not modulate the release of MIP-1alpha and TNF, this treatment (6 h) significantly increased the release of these mediators when AMs were further stimulated with LPS (increases of 47 and 21%, respectively). Further, LTD(4) pretreatment increased messenger RNA (mRNA) levels of MIP-1alpha and TNF. These effects of LTD(4) were abrogated by the presence of a LTD(4) receptor antagonist, Verlukast (MK-679), showing the specificity of LTD(4). Interestingly, LTD(4) treatment significantly increased the release of NO by LPS-stimulated AMs without modulating mRNA levels of the inducible NO synthase. Our data suggest that LTD(4) primes AMs to release more MIP-1alpha, TNF, and NO after stimulation. Thus, in addition to its potent bronchoconstrictor effect, LTD(4) may participate in the inflammatory process seen in asthma by potentiating the production of proinflammatory mediators by AMs during immunologic stimuli.
Ménard
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Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Ste-Foy, Quebec, Canada.
Bissonnette
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EY
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D018836:Inflammation Mediators / Q000378:metabolism*; D017998:Leukotriene D4 / Q000502:physiology*; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D017931:DNA Primers; D018836:Inflammation Mediators; D019402:Macrophage Inflammatory Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D017998:Leukotriene D4