HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Published online before print June 3, 2004

This Article Full Text (Reprint (PDF)) All Versions of this Article: jlb.0104005v1 76/3/641    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krakstad, C. Articles by Døskeland, S. O. Search for Related Content PubMed PubMed Citation Articles by Krakstad, C. Articles by Døskeland, S. O.

© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0104005

Received for publication January 6, 2004.
Revised April 6, 2004.
Accepted for publication May 4, 2004.

Article

cAMP protects neutrophils against TNF--induced apoptosis by activation of cAMP-dependent protein kinase, independently of exchange protein directly activated by cAMP (Epac)

Cell Biology Research Group, Department of Anatomy and Cell Biology, University of Bergen, Norway

^@ To whom correspondence should be addressed. E-mail: stein.doskeland{at}iac.uib.no.

	Abstract

It is unclear by which receptor cyclic adenosine monophosphate (cAMP) acts to promote neutrophil survival. We found that 8-(4-chlorophenylthio)-2`-O-methyl-cAMP, a specific activator of the recently discovered cAMP receptor, cAMP-regulated guanosine 5`-triphosphate exchange protein directly activated by cAMP, failed to protect human neutrophils from cell death. In contrast, specific activators of cAMP-dependent protein kinase type I (cA-PKI) could protect against death receptor [tumor necrosis factor receptor 1 (TNFR-1), Fas]-mediated apoptosis as well as cycloheximide-accelerated "spontaneous" apoptosis. A novel "caged" cA-PK-activating analog, 8-bromo (8-Br)-acetoxymethyl-cAMP, was more than 20-fold more potent than 8-Br-cAMP to protect neutrophils challenged with TNF- against apoptosis. This analog acted more rapidly than forskolin (which increases the endogenous cAMP production) and allowed us to demonstrate that cA-PK must be activated during the first 10 min after TNF- challenge to protect against apoptosis. The protective effect was mediated solely through cA-PK activation, as it was abolished by the cA-PKI-directed inhibitor Rp-8-Br-cAMPS and the general cA-PK inhibitor H-89. Neutrophils not stimulated by cAMP-elevating agents showed increased apoptosis when exposed to the cA-PK inhibitors Rp-8-Br-cAMPS and H-89, suggesting that even moderate activation of cA-PK is sufficient to enhance neutrophil longevity and thereby contribute to neutrophil accumulation in chronic inflammation.

Key Words: apoptosis • inflammation • cytokine

This article has been cited by other articles:

				K. R. Vaughan, L. Stokes, L. R. Prince, H. M. Marriott, S. Meis, M. U. Kassack, C. D. Bingle, I. Sabroe, A. Surprenant, and M. K. B. Whyte Inhibition of Neutrophil Apoptosis by ATP Is Mediated by the P2Y11 Receptor J. Immunol., December 15, 2007; 179(12): 8544 - 8553. [Abstract] [Full Text] [PDF]

				T. Bryn, M. Mahic, J. M. Enserink, F. Schwede, E. M. Aandahl, and K. Tasken The Cyclic AMP-Epac1-Rap1 Pathway Is Dissociated from Regulation of Effector Functions in Monocytes but Acquires Immunoregulatory Function in Mature Macrophages. J. Immunol., June 15, 2006; 176(12): 7361 - 7370. [Abstract] [Full Text] [PDF]

				P. Goichberg, A. Kalinkovich, N. Borodovsky, M. Tesio, I. Petit, A. Nagler, I. Hardan, and T. Lapidot cAMP-induced PKC{zeta} activation increases functional CXCR4 expression on human CD34+ hematopoietic progenitors Blood, February 1, 2006; 107(3): 870 - 879. [Abstract] [Full Text] [PDF]

				S.-L. C. Jin, L. Lan, M. Zoudilova, and M. Conti Specific Role of Phosphodiesterase 4B in Lipopolysaccharide-Induced Signaling in Mouse Macrophages J. Immunol., August 1, 2005; 175(3): 1523 - 1531. [Abstract] [Full Text] [PDF]