Abstract
Macrophage-derived chemokine [CC chemokine ligand 22 (CCL22)] and thymus- and activation-regulated chemokine (CCL17) mediate cellular effects, principally by binding to their receptor CC chemokine receptor 4 (CCR4) and together, constitute a multifunctional chemokine/receptor system with homeostatic and inflammatory roles within the body. This study demonstrates that CCL22 and CCL17 stimulate pertussis toxin-sensitive elevation of intracellular calcium in the CEM leukemic T cell line and human peripheral blood-derived T helper type 2 (Th2) cells. Inhibition of phospholipase C (PLC) resulted in the abrogation of chemokine-mediated calcium mobilization. Chemokine-stimulated calcium responses were also abrogated completely by the inhibition of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptor-mediated calcium release. Chemotactic responses of CEM and human Th2 cells to CCL17 and CCL22 were similarly abrogated by inhibition of PLC and inhibition of novel, Ca2+-independent/diacylglycerol-dependent protein kinase C (PKC) isoforms. Inhibition of Ins(1,4,5)P3 receptor-mediated calcium release from intracellular stores had no effect on chemotactic responses to CCR4 ligands. Taken together, this study provides compelling evidence of an important role for PLC and diacylglycerol-dependent effector mechanisms (most likely involving novel PKC isoforms) in CCL17- and CCL22-stimulated, directional cell migration. In this regard, CCL22 stimulates phosphatidylinositol-3 kinase-independent phosphorylation of the novel delta isoform of PKC at threonine 505, situated within its activation loop--an event closely associated with increased catalytic activity.
Publication types
- Research Support, Non-U.S. Gov't
MeSH terms
- Acetophenones / pharmacology
- Benzopyrans / pharmacology
- Calcium / physiology
- Calcium Channels / physiology
- Calcium Signaling / drug effects
- Calcium Signaling / physiology
- Catalytic Domain
- Cell Line, Tumor / cytology
- Cell Line, Tumor / drug effects
- Cell Line, Tumor / physiology
- Chemokine CCL17
- Chemokine CCL22
- Chemokines, CC / genetics
- Chemokines, CC / physiology*
- Chemotaxis / drug effects
- Chemotaxis / physiology*
- Chromones / pharmacology
- Diglycerides / physiology
- Estrenes / pharmacology
- Humans
- Indoles / pharmacology
- Inositol 1,4,5-Trisphosphate / physiology
- Inositol 1,4,5-Trisphosphate Receptors
- Leukemia-Lymphoma, Adult T-Cell / pathology
- Morpholines / pharmacology
- Pertussis Toxin / pharmacology
- Phosphatidylinositol 3-Kinases / physiology
- Phosphatidylinositol Diacylglycerol-Lyase / antagonists & inhibitors
- Phosphatidylinositol Diacylglycerol-Lyase / physiology*
- Phosphoinositide-3 Kinase Inhibitors
- Phosphorylation
- Phosphothreonine / chemistry
- Protein Processing, Post-Translational / drug effects
- Protein Processing, Post-Translational / physiology*
- Pyrroles / pharmacology
- Pyrrolidinones / pharmacology
- Receptors, CCR4
- Receptors, Chemokine / physiology*
- Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
- Receptors, Cytoplasmic and Nuclear / physiology
- Recombinant Fusion Proteins / pharmacology
- T-Lymphocytes / cytology
- T-Lymphocytes / drug effects*
- Th2 Cells / cytology
- Th2 Cells / drug effects
Substances
- 1,2-diacylglycerol
- Acetophenones
- Benzopyrans
- CCL17 protein, human
- CCL22 protein, human
- CCR4 protein, human
- Calcium Channels
- Chemokine CCL17
- Chemokine CCL22
- Chemokines, CC
- Chromones
- Diglycerides
- Estrenes
- ITPR1 protein, human
- ITPR2 protein, human
- Indoles
- Inositol 1,4,5-Trisphosphate Receptors
- Morpholines
- Phosphoinositide-3 Kinase Inhibitors
- Pyrroles
- Pyrrolidinones
- Receptors, CCR4
- Receptors, Chemokine
- Receptors, Cytoplasmic and Nuclear
- Recombinant Fusion Proteins
- Phosphothreonine
- 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
- Ro 32-0432
- 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
- Inositol 1,4,5-Trisphosphate
- rottlerin
- Pertussis Toxin
- Phosphatidylinositol Diacylglycerol-Lyase
- Calcium