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 Fantuzzi, et al. 2008. Blood 111,3355-3363.

Student: Jui-In Kai (蓋如茵)                                                           Time: 14:00~15:00, Sep 17, 2008

Commentator: Shainn-Wei Wang (王憲威 博士)                          Place: Room 601

Abstract

        Macrophages are also the targets of human immunodeficiency virus (HIV) infection and play crtical roles in AIDS immunopathogenesis. Macrophages treated with HIV-1 glycoprotein 120 (gp120) show an increase in chemokine CCL2 (monocyte chematactic protein-1) secretion, which has been shown to recruit more target cells and enhance HIV-1 infection and replication [1]. However, the molecular mechanisms remain unclear. Signal transduction of bioactive lipids, usually generated from phospholipase-mediated phospholipid hydrolysis, serve as the intracellular second messengers and can be induced by a variety of stimulation such as chemical compounds, cytokines, chemokins, hormones, and viral products [2]. In this paper, the authers found that D609, a phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) inhibitor, blocked HIV-1 gp120-induced the specific production of CCL2, but not CCL3 (macrophage inflammatory protein-1alpha) or CCL4 (macrophage inflammatory protein-1beta), in human monocyte-derived macrophages. Treating HIV-1 gp120 activates PC-PLC, but not PC-PLD, via a concentration-dependent manner and time-dependently causes PC-PLC cellular relocalization from cytoplasm to plasma membrane. Blocking assay demonstrated that HIV-1 gp120-induced PC-PLC activation and CCL2 production were CCR5-dependent. However, treating cells with CCL4, a natural ligand of CCR5, showed no effects on PC-PLC enzymatic activity and cellular distribution as well as CCL2 production. Mechanistically, HIV-1 gp120 induced nuclear translocation of NF-kB p65 subunit, which is responsible for HIV-induced cytokine/chemokine production [3], was totally blocked by inhibiting PC-PLC. Further studies demonstrated the dependence of NF-kB on HIV-1 gp120-induced CCL2 production. Taken together, these results imply that activation of PC-PLC by HIV-1 gp120 is the critical signaling process leading to NF-kB activation followed by CCL2 secretion.

References

1.     Laura Fantuzzi, et al. 2003. Monocyte/macrophage-derived CC chemokines and their modulation by HIV-1 and cytokines: a complex network of interactions influencing viral replication and AIDS pathogenesis. Journal of Leukocyte Biology 74,719-725.

2.     Yoshinori Nozawa, et al. 2002. A thematic series on lipid signaling: prologue. Journal of Biochemistry 131,283-284.

3.     Wonkyu Choe, et al. 2002. Activation of NF-kappaB by R5 and X4 human immunodeficiency virus type 1 induces macrophage inflammatory protein 1alpha and tumor necrosis factor alpha in macrophages. Journal of Virology 76,5274-5277.