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

Bethel-Brown Crystal, Yao Honghong, Hu Guoku, Buch, Buch Shilpa

Description

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.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 426
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Bethel-Brown et al. Journal of Neuroinflammation 2012, 9 :262 http://www.jneuroinflammation.com/content/9/1/262

JOURNAL OF NEUROINFLAMMATION

R E S E A R C H Open Access Platelet-derived growth factor (PDGF)-BB- mediated induction of monocyte chemoattractant protein 1 in human astrocytes: implications for HIV-associated neuroinflammation Crystal Bethel-Brown 1 , Honghong Yao 1 , Guoku Hu 2 and Shilpa Buch 1,3*

Abstract 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 κ B (NF κ B). Chromatin immunoprecipitation (ChIP) assays demonstrated increased binding of NF κ B 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.

Background partly due to both increased survival rates of HIV- HIV-associated neurocognitive disorders (HAND) re- infected individuals and to the reduced ability of most of main a common complication of HIV infection affecting these drugs to cross the blood – brain barrier (BBB). up to 60% of infected individuals despite the use of anti- Among the factors involved in the pathogenesis of retroviral therapy (ART) [1]. With the advancement of HAND, influx of HIV-infected monocytes in response to ART the prevalence of HAND has actually increased, the chemokine monocyte chemoattractant protein 1 (MCP-1) via a breached endothelial barrier, plays a crit- * Correspondence: [e-mail] ical role in disease pathogenesis. MCP-1 plays a vital role 1 Department of Pharmacology and Experimental Neuroscience, University of in the recruitment of monocytes into the brain contrib- 3 N D e e b p ra ar s t kaMe t di o c f a P l h C a e r n m te a r c , ol O o m g a y h a a n , d NE Ex 6 p 8 e 1 ri 9 m 8, e U nt S a A lNeuroscience,985880 uting to neuroinflammation and BBB disruption [2,3]. Nebraska me M n edicalCo This chemokine has been extensively studied and is Omaha,NE68198-58 e 8 nt 0, er U ( S D A RC8011),UniversityfNebraskaMedicalCenter, expressed by a number of cell types including astrocytes, Full list of author information is available at the end of the article © 2012 Bethel-Brown et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.