Elafin prevents lipopolysaccharide-induced AP-1 and NF-kappaB activation via an effect on the ubiquitin-proteasome pathway.
The serine anti-protease elafin is expressed by monocytes, alveolar macrophages, neutrophils, and at mucosal surfaces and possesses antimicrobial activity. It is also known to reduce lipopolysaccharide-induced neutrophil influx into murine alveoli as well as to abrogate lipopolysaccharide-induced production of matrix metalloprotease 9, macrophage inhibitory protein 2, and tumor necrosis factor-alpha by as-yet unidentified mechanisms. In this report we have shown that elafin inhibits the lipopolysaccharide-induced production of monocyte chemoattractant protein-1 in monocytes by inhibiting AP-1 and NF-kappaB activation. Elafin prevented lipopolysaccharide-induced phosphorylation of AP-1, c-Jun, and JNK but had no effect on phosphorylation of p38. The lipopolysaccharide-induced degradation of IL-1R-associated kinase 1, IkappaBalpha, and IkappaBbeta was inhibited by elafin but phosphorylation of IkappaBalpha was unaffected. Polyubiquitinated protein including polyubiquitinated IkappaBalpha was shown to accumulate in the presence of elafin. These results suggest that inhibition by elafin of lipopolysaccharide-induced AP-1 and NF-kappaB activation occurs via an effect on the ubiquitin-proteasome pathway.
Butler
Marcus W
MW
Pulmonary Research Division, Department of Medicine, The Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
Robertson
Ian
I
Greene
Catherine M
CM
O'Neill
Shane J
SJ
Taggart
Clifford C
CC
McElvaney
Noel G
NG
D018932:Chemokine CCL2 / Q000378:metabolism*; D053492:Elafin / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D020298:U937 Cells; D025801:Ubiquitin / Q000378:metabolism*
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D053492:Elafin; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D025801:Ubiquitin; D048670:MAP Kinase Kinase 4; D046988:Proteasome Endopeptidase Complex