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 Blood, 1 April 2008, Vol. 111, No. 7, pp. 3355-3363.
Prepublished online as a Blood First Edition Paper on January 18, 2008; DOI 10.1182/blood-2007-08-104901.

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CHEMOKINES, CYTOKINES, AND INTERLEUKINS

Phosphatidylcholine-specific phospholipase C activation is required for CCR5-dependent, NF-kB–driven CCL2 secretion elicited in response to HIV-1 gp120 in human primary macrophages

Laura Fantuzzi1, Francesca Spadaro1, Cristina Purificato1, Serena Cecchetti1, Franca Podo1, Filippo Belardelli1, Sandra Gessani1, and Carlo Ramoni1

1 Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy

CCL2 (MCP-1) has been shown to enhance HIV-1 replication. The expression of this chemokine by macrophages is up-modulated as a consequence of viral infection or gp120 exposure. In this study, we show for the first time that the phosphatidylcholine-specific phospholipase C (PC-PLC) is required for the production of CCL2 triggered by gp120 in human monocyte-derived macrophages (MDMs). Using a combination of pharmacologic inhibition, confocal laser-scanner microscopy, and enzymatic activity assay, we demonstrate that R5 gp120 interaction with CCR5 activates PC-PLC, as assessed by a time-dependent modification of its subcellular distribution and a concentration-dependent increase of its enzymatic activity. Furthermore, PC-PLC is required for NF-kB–mediated CCL2 production triggered by R5 gp120. Notably, PC-PLC activation through CCR5 is specifically induced by gp120, since triggering CCR5 through its natural ligand CCL4 (MIP-1β) does not affect PC-PLC cellular distribution and enzymatic activity, as well as CCL2 secretion, thus suggesting that different signaling pathways can be activated through CCR5 interaction with HIV-1 or chemokine ligands. The identification of PC-PLC as a critical mediator of well-defined gp120-mediated effects in MDMs unravels a novel mechanism involved in bystander activation and may contribute to define potential therapeutic targets to block Env-triggered pathologic responses.


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