Secretory leucoprotease inhibitor prevents lipopolysaccharide-induced IkappaBalpha degradation without affecting phosphorylation or ubiquitination.
Secretory leucoprotease inhibitor (SLPI) is a non-glycosylated protein produced by epithelial cells, macrophages, and neutrophils and was initially identified as a serine protease inhibitor of the neutrophil proteases elastase and cathepsin G. In addition to its antiprotease activity, SLPI has been shown to exhibit anti-inflammatory properties including down-regulation of tumor necrosis factor-alpha expression by lipopolysaccharide (LPS) in monocytes, inhibition of NF-kappaB activation by IgG immune complexes in a rat model of acute lung injury, and prevention of human immunodeficiency virus infectivity in monocytic cells via as yet unidentified mechanisms. In this report we have shown that SLPI prevents LPS-induced NF-kappaB activation by inhibiting degradation of IkappaBalpha without affecting the LPS-induced phosphorylation and ubiquitination of IkappaBalpha. We have also demonstrated that SLPI prevents LPS-induced interleukin-1 receptor-associated kinase and IkappaBbeta degradation. In addition, we have demonstrated that oxidized SLPI, a variant of SLPI that has diminished antiprotease activity, cannot prevent LPS-induced NF-kappaB activation or Inhibitor kappaB alpha/beta degradation indicating that the anti-inflammatory effect of SLPI on the LPS-signaling pathway is dependent on its antiprotease activity. These results suggest that SLPI may be inhibiting proteasomal degradation of NF-kappaB regulatory proteins, an effect that is dependent on the antiprotease activity of SLPI.
Taggart
Clifford C
CC
Pulmonary Research Division, Department of Medicine, The Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. ctaggart@rcsi.ie
Greene
Catherine M
CM
McElvaney
Noel G
NG
O'Neill
Shane
S
D003546:Cysteine Endopeptidases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D009097:Multienzyme Complexes / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011494:Protein Kinases / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000494:pharmacology*; D053481:Secretory Leukocyte Peptidase Inhibitor; D020298:U937 Cells; D025801:Ubiquitin / Q000378:metabolism*
D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D009097:Multienzyme Complexes; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; C506816:Slpi protein, rat; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex