L-Arginine attenuates lipopolysaccharide-induced lung chemokine production

Chemokines stimulate the influx of leukocytes into tissues. Their productio n is regulated by nuclear factor-kappaB (NF-kappaB), an inducible transcrip tion factor under the control of inhibitory factor kappaB-alpha (I kappaB-a lpha). We have previously demonstrated that L-arginine (L-Arg) attenuates n eutrophil accumulation and pulmonary vascular injury after administration o f lipopolysaccharide (LPS). We hypothesized that L-Arg would attenuate the production of lung chemokines by stabilizing I kappaB-alpha and preventing NF-kappaB DNA binding. We examined the effect of L-Arg on chemokine product ion, IkB-alpha degradation, and NF-kappaB DNA binding in the lung after sys temic LPS. To block nitric oxide (NO) production, a NO synthase inhibitor w as given before L-Arg. LPS induced the production of chemokine protein and mRNA. L-Arg attenuated the production of chemokine protein and mRNA, preven ted the decrease in I kappaB-alpha levels, and inhibited NF-kappaB DNA bind ing. 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 i s mediated by stabilization of I kappaB-alpha levels and inhibition of NF-k appaB DNA binding.