The carboxyl-terminal fragment of alpha1-antitrypsin is present in atherosclerotic plaques and regulates inflammatory transcription factors in primary human monocytes.
alpha1-Antitrypsin (AAT) serine proteinase inhibitor is found in most biological fluids, diffuses into most tissues, and is an important factor in controlling tissue damage by proteases in inflammatory diseases such as atherosclerosis. We have previously reported that the C-terminal fragment (C-36) generated during the cleavage of AAT by proteinases forms amyloid fibrils which have biological effects unrelated to precursor functions. Here we show that the C-36 fragment is present in atherosclerotic plaques, particularly within the fibrous cap at the base of the lipid core. We also found that human monocyte stimulation with C-36 fibrils led to a strong activation of both peroxisome proliferator-activated receptors alpha and gamma (PPARalpha and PPARgamma) at 1, 2, and 18 h of cell culture. A parallel increase in the intracellular lipid accumulation was also observed. Furthermore, stimulation of monocytes with C-36 for 18 h led to activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) activation. These data for the first time demonstrate the peptide of AAT as a component of atherosclerotic plaques and as a novel activator of PPARalpha, PPARgamma, NF-kappaB, and AP-1 in cultured monocytes. Taken together, the effects of the peptide represent a new mechanism of monocyte activation that may be of importance not only in atherogenesis, but also in other inflammatory processes.
Dichtl
W
W
Department of Medicine, University Hospital Malmö, Malmö, 20502, Sweden.
Moraga
F
F
Ares
M P
MP
Crisby
M
M
Nilsson
J
J
Lindgren
S
S
Janciauskiene
S
S
D001161:Arteriosclerosis / Q000378:metabolism*; D001483:Base Sequence; D002339:Carotid Arteries / Q000166:cytology / Q000378:metabolism; D002470:Cell Survival; D017931:DNA Primers; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000378:metabolism*
D017931:DNA Primers; D018836:Inflammation Mediators; D010446:Peptide Fragments; D014157:Transcription Factors; D000515:alpha 1-Antitrypsin