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Published online before print April 13, 2006

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(Journal of Leukocyte Biology. 2006;79:1369-1380.)
© 2006 by Society for Leukocyte Biology

Evidence that phospholipase C-dependent, calcium-independent mechanisms are required for directional migration of T lymphocytes in response to the CCR4 ligands CCL17 and CCL22

Darran G. Cronshaw^*, Andreas Kouroumalis^*, Richard Parry^*, Adam Webb^*, Zarin Brown and Stephen G. Ward^*,1

^* Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Avon, United Kingdom; and
Novartis Horsham Research Centre, West Sussex, United Kingdom

¹Correspondence: Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath, Avon, UK BA2 7AY. E-mail: S.G.Ward{at}bath.ac.uk

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 isoform of PKC at threonine 505, situated within its activation loop—an event closely associated with increased catalytic activity.

Key Words: chemokines • signaling • chemotaxis • PKC

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