Cutting edge: a critical role of nitric [corrected] oxide in preventing inflammation upon apoptotic cell clearance.
Apoptotic cells are removed by phagocytes without causing inflammation. It remains largely unresolved whether anti-inflammatory mediators prevent neutrophil infiltration upon apoptotic cell clearance in vivo. In this study, we showed that, upon induction of apoptosis in the thymus by x-ray, inducible NO synthase knockout (KO) mice exhibited higher levels of neutrophil infiltration and production of MIP-2 and keratinocyte-derived chemokine (KC) in the thymus than wild-type (WT) mice. Furthermore, administration of NG-nitro-L-arginine methyl ester, an inhibitor of NO synthase, to x-irradiated WT mice increased the level of neutrophil infiltration to that of KO mice by the augmentation of MIP-2 and KC production. Additionally, thymic macrophages isolated from x-irradiated KO mice produced more MIP-2 and KC than those from WT mice. Thus, although apoptosis is believed to be noninflammatory, this is actually achieved by the production of immunosuppressive signals such as NO that counteract proinflammatory chemokines such as MIP-2 and KC.
Shibata
Takehiko
T
Department of Biomolecular Science, Faculty of Science, Toho University, Funabashi, Chiba, Japan.
Nagata
Kisaburo
K
Kobayashi
Yoshiro
Y
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis / Q000528:radiation effects; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000528:radiation effects; D018920:Coculture Techniques; D004195:Disease Models, Animal; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D008264:Macrophages / Q000378:metabolism / Q000528:radiation effects; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020556:Neutrophil Infiltration / Q000276:immunology / Q000528:radiation effects; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D014916:Whole-Body Irradiation