Nitric oxide-mediated cytotoxic effects of alveolar macrophages on transformed lung epithelial cells are independent of the beta 2 integrin-mediated intercellular adhesion.
It is known that murine macrophages produce nitric oxide (NO) when stimulated with lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma), and NO mediates the tumoricidal activity of activated macrophages. The present study was designed to investigate whether the intercellular adhesion is necessary for activated rat alveolar macrophages to exert the full cytotoxic effects. Rat alveolar macrophages produced NO dose dependently in response to either LPS or IFN-gamma, and caused DNA fragmentation in rat type II pneumocytes transformed with SV40 (SV40T2). Chemically produced NO also caused the DNA fragmentation and viability loss in SV40T2, and both of them were inhibited by a NO radical scavenger. The cytotoxicity of activated macrophages was reduced by NG-monomethyl-L-arginine, a competitive nitric synthase inhibitor, and neither superoxide dismutase nor catalase modulated the cytotoxicity. Although alveolar macrophages stimulated with either LPS or IFN-gamma caused DNA fragmentation of SV40T2, only LPS increased the intercellular adherence between macrophages and SV40T2. The intercellular adhesion was reduced by both anti-CD18 and anti-CD11a. However, those antibodies did not affect the cytotoxicity of LPS-stimulated macrophages. These results clearly indicate that NO-mediated cytotoxicity is caused predominantly by diffusion of NO, and the beta 2 integrin-mediated intercellular adhesion does not play an important role, if any, in activated macrophage-mediated cytotoxic effects on SV40T2.
Hirano
S
S
Regional Environment Division, National Institute for Environmental Studies, Ibaraki, Japan.
D000818:Animals; D018821:CD18 Antigens / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D002472:Cell Transformation, Viral; D053938:DNA Fragmentation; D004306:Dose-Response Relationship, Immunologic; D004847:Epithelial Cells / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018821:CD18 Antigens; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D007371:Interferon-gamma