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J. Biol. Chem., Vol. 282, Issue 12, 8573-8582, March 23, 2007

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₁-Antitrypsin, Old Dog, New Tricks

₁-ANTITRYPSIN EXERTS IN VITRO ANTI-INFLAMMATORY ACTIVITY IN HUMAN MONOCYTES BY ELEVATING cAMP^*

From the Department of Clinical Sciences, University Hospital Malmö, Lund University, SE-20502 Malmö, Sweden

Regulation of serine protease activity is considered to be the sole mechanism for the function of ₁-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- 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- 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.

Received for publication, August 21, 2006 , and in revised form, January 29, 2007.

^* This work was supported by grants from the Swedish Research Council, the ALTA award, The Heart-Lung Foundation, and The Thelma Zoega Foundation. 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: Dept. of Clinical Sciences, Wallenberg Laboratory, Malmö University Hospital, SE-20502 Malmö, Sweden. Tel.: 4640336155; Fax: 4640337041; E-mail: sabina.janciauskiene{at}med.lu.se.

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