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), 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 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.
α-Melanocyte-related tripeptide, Lys-d-Pro-Val, ameliorates endotoxin-induced nuclear factor κB translocation and activation: evidence for involvement of an interleukin-1β193–195 receptor antagonism in the alveolar epithelium
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John J. E. HADDAD, Ryszard LAUTERBACH, Nayef E. SAADÉ, Bared SAFIEH-GARABEDIAN, Stephen C. LAND; α-Melanocyte-related tripeptide, Lys-d-Pro-Val, ameliorates endotoxin-induced nuclear factor κB translocation and activation: evidence for involvement of an interleukin-1β193–195 receptor antagonism in the alveolar epithelium. Biochem J 1 April 2001; 355 (1): 29–38. doi: https://doi.org/10.1042/bj3550029
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