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Alpha-melanocyte-related tripeptide, Lys-d-Pro-Val, ameliorates endotoxin-induced nuclear factor kappaB translocation and activation: evidence for involvement of an interleukin-1beta193-195 receptor antagonism in the alveolar epithelium.
- Source :
-
The Biochemical journal [Biochem J] 2001 Apr 01; Vol. 355 (Pt 1), pp. 29-38. - Publication Year :
- 2001
-
Abstract
- The potential anti-inflammatory role of alpha-melanocyte-stimulating hormone (alpha-MSH)-related tripeptide, lysine(11)-D-proline-valine(13) (KDPV), an analogue of interleukin (IL)-1beta(193-195) and an antagonist of IL-1beta/prostaglandin E(2), is not well characterized in the alveolar epithelium. In a model of foetal alveolar type II epithelial cells in vitro, we showed that lipopolysaccharide endotoxin (LPS) differentially, but selectively, induced the nuclear subunit composition of nuclear factor kappaB(1) (NF-kappaB(1)) (p50), RelA (p65) and c-Rel (p75), in parallel to up-regulating the DNA-binding activity (supershift indicating the presence of the p50-p65 complex). LPS accelerated the degradation of inhibitory kappaB-alpha (IkappaB-alpha), accompanied by enhancing its phosphorylation in the cytosolic compartment but not in the nucleus. KDPV suppressed, in a dose-dependent manner, the nuclear localization of p50, p65 and p75, an effect that led to the subsequent inhibition of NF-kappaB activation. Interleukin-1 receptor antagonist (IL-1ra) decreased the nuclear abundance of p50, p65 and p75, and subsequently depressed the DNA-binding activity induced by LPS. Analysis of the mechanism involved in the KDPV- and IL-1ra-mediated inhibition of NF-kappaB nuclear localization revealed a reversal in IkappaB-alpha phosphorylation and degradation, followed by cytosolic accumulation. LPS induced endogenous IL-1beta biosynthesis in a time-dependent manner; the administration of exogenous recombinant human interleukin 1 (rhIL-1) resulted in a dose-dependent activation of NF-kappaB. KDPV and IL-1ra abrogated the effect of rhIL-1. Pretreatment with the non-steroidal anti-inflammatory drug (NSAID) indomethacin, an inhibitor of cyclo-oxygenase, blocked the LPS-induced activation of NF-kappaB. These results indicate the involvement of prostanoid-dependent (NSAID-sensitive) and IL-1-dependent (IL-1ra-sensitive) mechanisms mediating LPS-induced NF-kappaB translocation and activation, a pathway that is regulated, in part, by a negative feedback mechanism transduced through IkappaB-alpha, the major cytosolic inhibitor of NF-kappaB.
- Subjects :
- Animals
Anti-Inflammatory Agents, Non-Steroidal pharmacology
Cells, Cultured
DNA metabolism
Enzyme-Linked Immunosorbent Assay
Epithelial Cells drug effects
Epithelial Cells metabolism
Hydrolysis
Indomethacin pharmacology
Phosphorylation
Protein Transport
Pulmonary Alveoli metabolism
Rats
Rats, Sprague-Dawley
Receptors, Interleukin-1 antagonists & inhibitors
Lipopolysaccharides pharmacology
Melanocyte-Stimulating Hormones pharmacology
NF-kappa B metabolism
Peptide Fragments antagonists & inhibitors
Peptide Fragments pharmacology
Pulmonary Alveoli drug effects
Receptors, Interleukin-1 chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0264-6021
- Volume :
- 355
- Issue :
- Pt 1
- Database :
- MEDLINE
- Journal :
- The Biochemical journal
- Publication Type :
- Academic Journal
- Accession number :
- 11256945
- Full Text :
- https://doi.org/10.1042/0264-6021:3550029