Platelet-derived growth factor (PDGF)-BB-mediated induction of monocyte chemoattractant protein 1 in human astrocytes: Implications for HIV-associated neuroinflammation

Chemokine (c-c motif) ligand 2,also known as monocyte chemoattractant protein 1 (mcp-1) is an important factor for the pathogenesis of hiv-associated neurocognitive disorders (hand). the mechanisms of mcp-1-mediated neuropathogenesis,in part,revolve around its neuroinflammatory role and the recruitment of monocytes into the central nervous system (cns) via the disrupted blood-brain barrier (bbb). we have previously demonstrated that hiv-1/hiv-1 tat upregulate platelet-derived growth factor (pdgf)-bb,a known cerebrovascular permeant; subsequently,the present study was aimed at exploring the regulation of mcp-1 by pdgf-bb in astrocytes with implications in hand. specifically,the data herein demonstrate that exposure of human astrocytes to hiv-1 lai elevated pdgf-b and mcp-1 levels. furthermore,treating astrocytes with the human recombinant pdgf-bb protein significantly increased the production and release of mcp-1 at both the rna and protein levels. mcp-1 induction was regulated by activation of extracellular-signal-regulated kinase (erk)1/2,c-jun n-terminal kinase (jnk) and p38 mitogen-activated protein (map) kinases and phosphatidylinositol 3-kinase (pi3k)/akt pathways and the downstream transcription factor,nuclear factor κb (nfκb). chromatin immunoprecipitation (chip) assays demonstrated increased binding of nfκb to the human mcp-1 promoter following pdgf-bb exposure. conditioned media from pdgf-bb-treated astrocytes increased monocyte transmigration through human brain microvascular endothelial cells (hbmecs),an effect that was blocked by sti-571,a tyrosine kinase inhibitor (pdgf receptor (pdgf-r) blocker). pdgf-bb-mediated release of mcp-1 was critical for increased permeability in an in vitro bbb model as evidenced by blocking antibody assays. since mcp-1 is linked to disease severity,understanding its modulation by pdgf-bb could aid in understanding the proinflammatory responses in hand. these results suggest that astrocyte activation by pdgf-bb exaggerates monocyte recruitment into the brain via mcp-1 and underscores the critical role astrocytes play in hand. © 2012 bethel-brown et al.; licensee biomed central ltd.