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

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.

p52Shc is required for CXCR4-dependent signaling and chemotaxis in T cells

“…The latter would further enhance Erk1/2 activation. PLC␥, another ZAP-70 substrate also coupled to chemokine receptors, 51 may further contribute to Erk1/2 activation through the diacylglycerol-dependent Ras exchange factor RasGRP. 52 The early role of p52Shc in CXCR4 signaling, and the resulting impairment of ZAP-70 activation when its recruitment to p52Shc is prevented, could fully account for pleiotropic inhibitory effects of Shc1F and Shc2F on the CXCR4 cascade.…”

CCL22/Macrophage-derived Chemokine Expression in Apolipoprotein E-deficient Mice and Effects of Histamine in the Setting of Atherosclerosis

“…The expression of CCL22 increases with the progression of atherosclerosis and accumulation of macrophages, and histamine accelerates the expression of CCL22 in monocytes and leads to the differentiation of monocytes into macrophages following stimulation of the H2 receptor. This cycle of events may contribute to the onset of early atherosclerosis by recruiting monocytes and T-cells 1,29) and also promotes the progression of atherosclerosis. In fact, the apoE-KO mice had large atheromas and high levels of serum CCL22 compared with the DKO mice and apoE/H2R double-knockout mice (personal communication, by Sasaguri Y. et al from the University of Occupational and Environmental Health, Kitakyusyu, Japan).…”

CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges

“…In a subsequent study using CEM cells, both CCL17 and CCL22 were found to induce calcium flux in a PLC-dependent manner (Cronshaw et al, 2006). Calcium release was found to be dependent on inositol trisphosphate (IP 3 )-sensitive store operation.…”