Corticosteroid inhibition of macrophage inflammatory protein-1 alpha in human monocytes and alveolar macrophages.
One of the major inducible cytokines secreted by mononuclear phagocytes is macrophage inflammatory protein 1 (MIP-1), which consists of two homologous polypeptides, MIP-1 alpha and MIP-1 beta. MIP-1 alpha possesses chemotactic and stimulatory activities for lymphocytes, eosinophils, and monocytes and may play a role in various pulmonary inflammatory conditions. We investigated the expression and release of MIP-1 alpha from human peripheral blood monocytes (PBM) and alveolar macrophages (AM) after stimulation with lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha, and interferon-gamma and the inhibitory effects of corticosteroids. LPS and IL-1 beta only enhanced MIP-1 alpha mRNA and protein in a dose- and time-dependent fashion. Dexamethasone (10(-9) to 10(-4) M) inhibited the basal and induced production and expression of MIP-1 alpha. In PBM, dexamethasone (10(-6) M) reduced LPS- and IL-1 beta-stimulated production of MIP-1 alpha protein by 50 and 63%, respectively, maximally at 24 h, whereas the inhibition of mRNA expression occurred maximally at 4 h. Similar trends were observed for AM. MIP-1 alpha mRNA decay was only slightly decreased in the presence of dexamethasone. Inhibition of LPS-induced MIP-1 alpha mRNA by dexamethasone was attenuated by the protein synthesis inhibitor cycloheximide, indicating the involvement of a protein intermediate. Corticosteroids are a potent inhibitor of IL-1 beta- and LPS-induced expression of MIP-1 alpha through mechanisms involving mainly inhibition of transcription and to a minor degree by reducing mRNA stability. Corticosteroids may be effective anti-inflammatory agents by preventing the expression of chemokines such as MIP-1 alpha.
D001483:Base Sequence; D054407:Chemokine CCL4; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins; D016676:Macrophages, Alveolar / Q000378:metabolism*; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism*; D015846:Monokines / Q000037:antagonists & inhibitors* / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
D054407:Chemokine CCL4; D016207:Cytokines; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D015335:Molecular Probes; D015846:Monokines; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D003907:Dexamethasone; D003513:Cycloheximide