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.
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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