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J. Biol. Chem., Vol. 280, Issue 37, 32459-32467, September 16, 2005

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"Host Tissue Damage" Signal ATP Promotes Non-directional Migration and Negatively Regulates Toll-like Receptor Signaling in Human Monocytes^*

Andreas Kaufmann, Boris Musset, Sven H. Limberg, Vijay Renigunta, Rainer Sus, Alexander H. Dalpke¶, Klaus M. Heeg¶, Bernard Robaye||, and Peter J. Hanley1

From the Institute of Immunology, Marburg University, Robert-Koch-Strasse 17, 35037 Marburg, Germany, the Institute of Physiology, Marburg University, Deutschhausstrasse 2, 35037 Marburg, Germany, ^¶Hygiene-Institut, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany, and ^||Institute of Interdisciplinary Research, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, 6041 Gosselies, Belgium

The activation of Toll-like receptors (TLRs) by lipopolysaccharide or other ligands evokes a proinflammatory immune response, which is not only capable of clearing invading pathogens but can also inflict damage to host tissues. It is therefore important to prevent an overshoot of the TLR-induced response where necessary, and here we show that extracellular ATP is capable of doing this in human monocytes. Using reverse transcription-PCR, we showed that monocytes express P2Y₁, P2Y₂, P2Y₄, P2Y₁₁, and P2Y₁₃ receptors, as well as several P2X receptors. To elucidate the function of these receptors, we first studied Ca²⁺ signaling in single cells. ATP or UTP induced a biphasic increase in cytosolic Ca²⁺, which corresponded to internal Ca²⁺ release followed by activation of store-operated Ca²⁺ entry. The evoked Ca²⁺ signals stimulated Ca²⁺-activated K⁺ channels, producing transient membrane hyperpolarization. In addition, ATP promoted cytoskeleton reorganization and cell migration; however, unlike chemoattractants, the migration was non-directional and further analysis showed that ATP did not activate Akt, essential for sensing gradients. When TLR2, TLR4, or TLR2/6 were stimulated with their respective ligands, ATPS profoundly inhibited secretion of proinflammatory cytokines (tumor necrosis factor- and monocyte chemoattractant protein-1) but increased the production of interleukin-10, an anti-inflammatory cytokine. In radioimmune assays, we found that ATP (or ATPS) strongly increased cAMP levels, and, moreover, the TLR-response was inhibited by forskolin, whereas UTP neither increased cAMP nor inhibited the TLR-response. Thus, our data suggest that ATP promotes non-directional migration and, importantly, acts as a "host tissue damage" signal via the G_s protein-coupled P2Y₁₁ receptor and increased cAMP to negatively regulate TLR signaling.

Received for publication, May 13, 2005 , and in revised form, June 24, 2005.

^* This project was supported by a grant from the Kempkes-Stiftung (to P. J. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental movie.

¹ To whom correspondence should be addressed. Tel.: 49-6421-286-6546; Fax: 49-6421-286-8960; E-mail: hanley{at}mailer.uni-marburg.de.

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