CRL-1072 enhances antimycobacterial activity of human macrophages through interleukin-8.
CRL-1072 is a poloxamer surfactant that kills mycobacteria more effectively within macrophages than in broth cultures. Human macrophages treated with CRL-1072 synthesized interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in a dose-dependent manner. About 3000 pg of IL-8 per million human macrophages accumulated in cultures treated with 100-1500 ng of poloxamer, with mRNA message for IL-8 induced as early as 2 h. As macrophages do not have IL-RA receptors, a transwell culture was used to study the chemotactic and activating effects of IL-8 between CRL-1072-treated human macrophage effectors and polymorphonuclear neutrophil (PMN) targets. PMN were activated by IL-8 and secreted hydrogen peroxide and myeloperoxidase (MPO). MPO derived from PMN, in turn, activated monocytes for an enhanced killing of intracellular Mycobacterium avium. The ability of CRL-1072 to modulate macrophage-mediated activation of neutrophils and receive a feedback activation signal may form one mechanism by which its antimycobacterial activity is achieved in vivo.
Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center, Houston 77030, USA. jagannath@casper.med.uth.tmc.edu
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D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008826:Microbial Sensitivity Tests; D009000:Monocytes / Q000187:drug effects; D009162:Mycobacterium avium / Q000187:drug effects* / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects; D009195:Peroxidase / Q000097:blood; D020442:Poloxamer / Q000627:therapeutic use*; D013501:Surface-Active Agents / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020298:U937 Cells
D016209:Interleukin-8; D013501:Surface-Active Agents; D014409:Tumor Necrosis Factor-alpha; D020442:Poloxamer; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006861:Hydrogen Peroxide; D009195:Peroxidase