Role of CXC chemokines in the enhancement of LPS-induced neutrophil accumulation in the lung of mice by dexamethasone.
Lipopolysaccharide (LPS)-induced multiple organ injury was mediated in part by a transcription factor, nuclear factor-kappaB (NF-kappaB). Mice were pretreated with dexamethasone (DEX), an inhibitor of NF-kappaB activation, to elucidate its effects on LPS-induced early responses in vivo. Early responses measured 1 h after intraperitoneal LPS administration at a dose of 1 mg/kg were (1) neutrophil accumulation in the tissues, (2) neutrophil degranulation, and (3) protein and mRNA expressions of tumor necrosis factor-alpha (TNF-alpha) and ELR(+) CXC chemokines [macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC)]. Treatment with DEX before LPS administration suppressed NF-kappaB activation and plasma TNF-alpha levels almost to undetectable levels, but enhanced neutrophil accumulation and augmented MIP-2 levels in the lung. The suppression of plasma TNF-alpha levels by pretreatment with an anti-TNF-alpha antibody did not enhance LPS-induced neutrophil accumulation in the lung. These results demonstrate that the enhancement of LPS-induced neutrophil accumulation by DEX might be mediated by MIP-2 and not by TNF-alpha.
Aoki
Kimiko
K
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. kaoki@pharm.showa-u.ac.jp
Ishida
Yumiko
Y
Kikuta
Nana
N
Kawai
Hiroe
H
Kuroiwa
Mie
M
Sato
Hitoshi
H
D000818:Animals; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019743:Chemokines, CXC / Q000502:physiology*; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D002634:Chemotaxis, Leukocyte; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D005938:Glucocorticoids / Q000494:pharmacology*; D006133:Growth Substances / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology*; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D005938:Glucocorticoids; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9