α-Melanocyte-related tripeptide, Lys-D-Pro-Val, ameliorates endotoxin-induced nuclear factor κB translocation and activation: evidence for involvement of an interleukin-1β_193-195 receptor antagonism in the alveolar epithelium

TY - JOUR

T1 - α-Melanocyte-related tripeptide, Lys-D-Pro-Val, ameliorates endotoxin-induced nuclear factor κB translocation and activation

T2 - evidence for involvement of an interleukin-1β193-195 receptor antagonism in the alveolar epithelium

AU - Haddad, John J..E.

AU - Lauterbach, Ryszard

AU - Saadé, Nayef E.

AU - Safieh-Garabedian, Bared

AU - Land, Stephen C.

PY - 2001/4/1

Y1 - 2001/4/1

N2 - The potential anti-inflammatory role of α-melanocyte-stimulating hormone (α-MSH)-related tripeptide, lysine11-D-proline-valine13 (KDPV), an analogue of interleukin (IL)-1β193-195 and an antagonist- of IL-1β/prostaglandin E2, 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 κB1 (NF-κB1) (p50), Re1A (p65) and c-Re1 (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 κB-α (IκB-α), 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-κB 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-κB nuclear localization revealed a reversal in IκB-α phosphorylation and degradation, followed by cytosolic accumulation. LPS induced endogenous IL-1β biosynthesis in a time-dependent manner; the administration of exogenous recombinant human interleukin 1 (rhIL-1) resulted in a dose-dependent activation of NF-κB. 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-κB. These results indicate the involvement of prostanoid-dependent (NSAID-sensitive) and IL:1-dependent (IL-1ra-sensitive) mechanisms mediating LPS-induced NF-κB translocation and activation, a pathway that is regulated, in part, by a negative feedback mechanism transduced through IκB-α, the major cytosolic inhibitor of NF-κB.

AB - The potential anti-inflammatory role of α-melanocyte-stimulating hormone (α-MSH)-related tripeptide, lysine11-D-proline-valine13 (KDPV), an analogue of interleukin (IL)-1β193-195 and an antagonist- of IL-1β/prostaglandin E2, 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 κB1 (NF-κB1) (p50), Re1A (p65) and c-Re1 (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 κB-α (IκB-α), 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-κB 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-κB nuclear localization revealed a reversal in IκB-α phosphorylation and degradation, followed by cytosolic accumulation. LPS induced endogenous IL-1β biosynthesis in a time-dependent manner; the administration of exogenous recombinant human interleukin 1 (rhIL-1) resulted in a dose-dependent activation of NF-κB. 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-κB. These results indicate the involvement of prostanoid-dependent (NSAID-sensitive) and IL:1-dependent (IL-1ra-sensitive) mechanisms mediating LPS-induced NF-κB translocation and activation, a pathway that is regulated, in part, by a negative feedback mechanism transduced through IκB-α, the major cytosolic inhibitor of NF-κB.

KW - Cytokine

KW - Inhibitory κB-α

KW - Pathophysiology

KW - Prostaglandin

KW - α-melanocyte-stimulating hormone

UR - https://www.scopus.com/pages/publications/0035310404

U2 - 10.1042/bj3550029

DO - 10.1042/bj3550029

M3 - Article

C2 - 11256945

AN - SCOPUS:0035310404

SN - 0264-6021

VL - 355

SP - 29

EP - 38

JO - Biochemical Journal

JF - Biochemical Journal

IS - 1

ER -