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J. Biol. Chem., Vol. 281, Issue 46, 34730-34735, November 17, 2006

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Elafin Prevents Lipopolysaccharide-induced AP-1 and NF-B Activation via an Effect on the Ubiquitin-Proteasome Pathway^*

From the Pulmonary Research Division, Department of Medicine, The Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland

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- 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-B 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, IB, and IB was inhibited by elafin but phosphorylation of IB was unaffected. Polyubiquitinated protein including polyubiquitinated IB was shown to accumulate in the presence of elafin. These results suggest that inhibition by elafin of lipopolysaccharide-induced AP-1 and NF-B activation occurs via an effect on the ubiquitin-proteasome pathway.

Received for publication, May 19, 2006 , and in revised form, September 14, 2006.

^* This work was funded by the American Alpha One Foundation (RO3-18) (to C. T.), Health Research Board of Ireland, and the Research Committee of The Royal College of Surgeons in Ireland. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Pulmonary Research Division, Dept. of Medicine, The Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. Tel.: 353-1-8093712; Fax: 353-1-8093808; E-mail: ctaggart{at}rcsi.ie.

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