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"Host tissue damage" signal ATP promotes non-directional migration and negatively regulates toll-like receptor signaling in human monocytes.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2005 Sep 16; Vol. 280 (37), pp. 32459-67. Date of Electronic Publication: 2005 Jul 19. - Publication Year :
- 2005
-
Abstract
- 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 P2Y(1), P2Y(2), P2Y(4), P2Y(11), and P2Y(13) receptors, as well as several P2X receptors. To elucidate the function of these receptors, we first studied Ca(2+) signaling in single cells. ATP or UTP induced a biphasic increase in cytosolic Ca(2+), which corresponded to internal Ca(2+) release followed by activation of store-operated Ca(2+) entry. The evoked Ca(2+) signals stimulated Ca(2+)-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, ATPgammaS profoundly inhibited secretion of proinflammatory cytokines (tumor necrosis factor-alpha and monocyte chemoattractant protein-1) but increased the production of interleukin-10, an anti-inflammatory cytokine. In radioimmune assays, we found that ATP (or ATPgammaS) 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 P2Y(11) receptor and increased cAMP to negatively regulate TLR signaling.
- Subjects :
- Adenosine Triphosphate analogs & derivatives
Adenosine Triphosphate chemistry
Animals
Anti-Inflammatory Agents pharmacology
Blotting, Western
Calcium metabolism
Cell Movement
Cell Survival
Cyclic AMP metabolism
Cytokines metabolism
Cytoskeleton metabolism
Dose-Response Relationship, Drug
Egtazic Acid pharmacology
Humans
Inflammation
Influenza A virus metabolism
Interleukin-10 metabolism
Ligands
Lipopolysaccharide Receptors biosynthesis
Models, Biological
Monocytes metabolism
Patch-Clamp Techniques
Potassium metabolism
Radioimmunoassay
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Toll-Like Receptor 2
Toll-Like Receptor 4
Toll-Like Receptor 6
Toll-Like Receptors
Uridine Triphosphate chemistry
Uridine Triphosphate metabolism
Adenosine Triphosphate metabolism
Gene Expression Regulation
Membrane Glycoproteins metabolism
Monocytes cytology
Receptors, Cell Surface metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 280
- Issue :
- 37
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16030017
- Full Text :
- https://doi.org/10.1074/jbc.M505301200