Alpha1-antitrypsin, old dog, new tricks. Alpha1-antitrypsin exerts in vitro anti-inflammatory activity in human monocytes by elevating cAMP.
Regulation of serine protease activity is considered to be the sole mechanism for the function of alpha1-antitrypsin (AAT). However, recent reports of the anti-inflammatory effects of AAT are hard to reconcile with this classical mechanism. We discovered that two key activities of AAT in vitro, namely inhibition of endotoxin-stimulated tumor necrosis factor-alpha and enhancement of interleukin-10 in human monocytes, are mediated by an elevation of cAMP and activation of cAMP-dependent protein kinase A. As expected with this type of mechanism, the AAT-mediated rise in cAMP and the impact on endotoxin-stimulated tumor necrosis factor-alpha and interleukin-10 was enhanced when the catabolism of cAMP was blocked by the phosphodiesterase inhibitor rolipram. These effects were still observed with modified forms of AAT lacking protease inhibitor activity.
Janciauskiene
Sabina M
SM
Department of Clinical Sciences, University Hospital Malmö, Lund University, SE-20502 Malmö, Sweden. sabina.janciauskiene@med.lu.se
Nita
Izabela M
IM
Stevens
Tim
T
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004731:Endotoxins / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000737:chemistry* / Q000502:physiology*
D000893:Anti-Inflammatory Agents; D004731:Endotoxins; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D016753:Interleukin-10; C017759:9-(tetrahydro-2-furyl)-adenine; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000225:Adenine; D020889:Rolipram