L-arginine attenuates lipopolysaccharide-induced lung chemokine production.
Chemokines stimulate the influx of leukocytes into tissues. Their production is regulated by nuclear factor-kappaB (NF-kappaB), an inducible transcription factor under the control of inhibitory factor kappaB-alpha (IkappaB-alpha). We have previously demonstrated that L-arginine (L-Arg) attenuates neutrophil accumulation and pulmonary vascular injury after administration of lipopolysaccharide (LPS). We hypothesized that L-Arg would attenuate the production of lung chemokines by stabilizing IkappaB-alpha and preventing NF-kappaB DNA binding. We examined the effect of L-Arg on chemokine production, IkappaB-alpha degradation, and NF-kappaB DNA binding in the lung after systemic LPS. To block nitric oxide (NO) production, a NO synthase inhibitor was given before L-Arg. LPS induced the production of chemokine protein and mRNA. L-Arg attenuated the production of chemokine protein and mRNA, prevented the decrease in IkappaB-alpha levels, and inhibited NF-kappaB DNA binding. NO synthase inhibition abolished the effects of L-Arg on all measured parameters. Our results suggest that L-Arg abrogates chemokine protein and mRNA production in rat lung after LPS. This effect is dependent on NO and is mediated by stabilization of IkappaB-alpha levels and inhibition of NF-kappaB DNA binding.
Calkins
C M
CM
Department of Surgery, University of Colorado Health Sciences Center and The Veterans Affairs Hospital, Denver, Colorado 80262, USA.
Bensard
D D
DD
Heimbach
J K
JK
Meng
X
X
Shames
B D
BD
Pulido
E J
EJ
McIntyre
R C
RC
D000818:Animals; D001120:Arginine / Q000097:blood / Q000494:pharmacology*; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C513297:Cxcl1 protein, rat; C404915:Cxcl2 protein, mouse; C513296:Cxcl2 protein, rat; D006133:Growth Substances; D020672:I-kappa B Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D004247:DNA; D001120:Arginine