Doxycycline protects serum alpha-1-antitrypsin from human neutrophil collagenase.
Interstitial collagenases, members of the matrix metalloproteinase family, are key initiators of collagen destruction during various disorders such as rheumatoid arthritis. Recently interstitial collagenases were found to efficiently degrade an additional non-collagenous substrate, the serum alpha-1-antitrypsin (AAT also called alpha-1-proteinase inhibitor or serpin). Serpins are major endogenous inhibitors of serine proteinases, particularly neutrophil elastase. Of relevance to neutrophil-mediated collagen degradation, the tetracycline family of antibiotics are now known to inhibit inhibit mammalian collagenases by a mechanism unrelated to their antimicrobial activity. This study identifies an additional mechanism by which tetracyclines may retard tissue breakdown during inflammatory diseases. Doxycycline, added to the reaction mixture as in concentrations as low as 10 microM, which correspond to levels of the drug readily achieved in vivo, produced detectable inhibition of serpinase activity of neutrophil collagenase, although levels of 50-100 microM or greater were required to reduce AAT degradation more than 75%. The concentration of doxycycline to inhibit 50% (IC50 of serpinase activity) of AAT degradation by neutrophil collagenase was found to approximate 20 microM, a value similar to the IC50 for doxycycline required to inhibit collagen degradation by neutrophil collagenase. Doxycycline was also found to inhibit at cell level neutrophil-mediated degradation of AAT. The protection of bodies' AAT-shield from serpinolytic activity of collagenase would result in inhibition of serine proteinases such as neutrophil elastase. Tetracyclines may thus protect matrix constituents from a wider spectrum of neutral proteases than previously recognized, not just from the matrix metalloproteinases collagenase and gelatinase.
Sorsa
T
T
Department of Periodontology, University of Helsinki, Finland.
Konttinen
Y T
YT
Lindy
O
O
Suomalainen
K
K
Ingman
T
T
Saari
H
H
Halinen
S
S
Lee
H M
HM
Golub
L M
LM
Hall
J
J
D017364:Collagenases / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D061965:Matrix Metalloproteinase Inhibitors; D009504:Neutrophils / Q000201:enzymology*; D015843:Serpins / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000378:metabolism*
D061965:Matrix Metalloproteinase Inhibitors; D015843:Serpins; D000515:alpha 1-Antitrypsin; D017364:Collagenases; D004318:Doxycycline