NF-κB involvement in the induction of high affinity CAT-2 in lipopolysaccharide-stimulated rat lungs
Endotoxemia stimulates nitric oxide (NO) biosynthesis through induction of inducible NO synthase (iNOS). Cellular uptake ofl-arginine, the sole substrate for iNOS, is an important mechanism regulating NO biosynthesis by iNOS. The isozymes of type-2 cationic amino acid transporters, including CAT-2, CAT-2A, and CAT-2B, constitute the most important pathways responsible for trans-membranel-arginine transportation. Therefore, regulation of CAT-2 isozymes expression may constitute one of the downstream regulatory pathways that control iNOS activity. We investigated the time course of enzyme induction and the role of nuclear factor-κB (NF-κB) in CAT-2 isozymes expression in lipopolysaccharide-(LPS) treated rat lungs. Methods:
Adult male Sprague–Dawley rats were randomly given intravenous injections of normal saline (N/S), LPS, LPS plus NF-κB inhibitor pre-treatment (PDTC, dexamethasone, or salicylate), or an NF-κB inhibitor alone. The rats were sacrificed at different times after injection and enzyme expression and lung injury were examined. Pulmonary and systemic NO production were also measured. Results:
LPS co-induced iNOS, CAT-2, and CAT-2B but not CAT-2A expression in the lungs. Furthermore, NF-κB actively participated in LPS-induction of iNOS, CAT-2, and CAT-2B. LPS induced pulmonary and systemic NO overproduction and resulted in lung injuries. Attenuation of LPS-induced iNOS, CAT-2, and CAT-2B induction significantly inhibited NO biosynthesis and lessened lung injury. Conclusion:
NF-κB actively participates in the induction of CAT-2 and CAT-2B in intact animals. Our data further support the idea that CAT-2 and CAT-2B are crucial in regulating iNOS activity.
Document Type: Research Article
Affiliations: 1: Taipei Medical University College of Nursing, 2: Chest Medicine, Mackay Memorial Hospital; Taipei, Taiwan, 3: Department of Anesthesiology, University of Louisville, Louisville, KY, 4: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL, and 5: Department of Child Health, University of Missouri, Columbia, MO, USA 6: Institute of Pharmacology, National Yang-Ming University,
Publication date: September 1, 2004