TY - JOUR
T1 - HIV-1-infected and/or immune-activated macrophages regulate astrocyte CXCL8 production through IL-1β and TNF-α
T2 - Involvement of mitogen-activated protein kinases and protein kinase R
AU - Zheng, Jialin C.
AU - Huang, Yunlong
AU - Tang, Kang
AU - Cui, Min
AU - Niemann, Doug
AU - Lopez, Alicia
AU - Morgello, Susan
AU - Chen, Shengdi
N1 - Funding Information:
This work was supported in part by research grants by the National Institutes of Health: R01 NS 41858, R21 MH083525, P20 RR15635 and P01 NS043985 to JZ. We kindly acknowledge Dr. Anuja Ghorpade, Mr. Matthew Beaver, and Ms. Li Wu who provided technical support for this work. Dr. Howard E. Gendelman, Ms. Angelique Walstrom, Mr. Nathan Erdmann, Ms. Agnes Constantino, and Ms. Tess Eidem provided valuable comments and suggestions about the manuscript. Ms. Julie Ditter, Johna Belling, Robin Taylor, Myhanh Che, Na Ly and Emilie Scoggins provided outstanding administrative support.
PY - 2008/8/30
Y1 - 2008/8/30
N2 - Monocyte infiltration is an important pathogenic event in human immunodeficiency virus type one (HIV-1) associated dementia (HAD). CXCL8 (Interleukin 8, IL-8), a CXC chemokine that elicits chemotaxis of neutrophils, has recently been found to recruit monocytes or synergistically enhance CCL2-mediated monocyte migration. In this report, we demonstrate CXCL8 levels in the cerebrospinal fluid of HAD patients are higher than HIV-1 seropositive patients without neurological impairment. The underlying mechanisms regulating CXCL8 production during disease are not completely understood. We investigated the role of HIV-1-infected and immune-competent macrophages, the principal target cell and mediator of neuronal injury in HAD, in regulating astrocyte CXCL8 production. Immune-activated and HIV-1-infected human monocyte-derived-macrophages (MDM) conditioned media (MCM) induced production of CXCL8 by human astrocytes. This CXCL8 production was dependent on MDM IL-1β and TNF-α production following viral and immune activation. CXCL8 production was reduced by inhibitors for mitogen-activated protein kinases (MAPKs), including p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK1/2). Moreover, prolonged IL-1β or TNF-α treatment activated double-stranded RNA-activated protein kinase (PKR). Inhibition of PKR prevented elevated CXCL8 production in astrocytes. We conclude that IL-1β and TNF-α, produced from HIV-1-infected and immune-competent macrophages, are critical in astrocyte CXCL8 production. Multiple protein kinases, including p38, JNK, ERK1/2, and PKR, participate in the inflammatory response of astrocytes. These observations will help to identify effective therapeutic strategies to reduce high-levels of CXCL8-mediated CNS inflammation during HAD.
AB - Monocyte infiltration is an important pathogenic event in human immunodeficiency virus type one (HIV-1) associated dementia (HAD). CXCL8 (Interleukin 8, IL-8), a CXC chemokine that elicits chemotaxis of neutrophils, has recently been found to recruit monocytes or synergistically enhance CCL2-mediated monocyte migration. In this report, we demonstrate CXCL8 levels in the cerebrospinal fluid of HAD patients are higher than HIV-1 seropositive patients without neurological impairment. The underlying mechanisms regulating CXCL8 production during disease are not completely understood. We investigated the role of HIV-1-infected and immune-competent macrophages, the principal target cell and mediator of neuronal injury in HAD, in regulating astrocyte CXCL8 production. Immune-activated and HIV-1-infected human monocyte-derived-macrophages (MDM) conditioned media (MCM) induced production of CXCL8 by human astrocytes. This CXCL8 production was dependent on MDM IL-1β and TNF-α production following viral and immune activation. CXCL8 production was reduced by inhibitors for mitogen-activated protein kinases (MAPKs), including p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK1/2). Moreover, prolonged IL-1β or TNF-α treatment activated double-stranded RNA-activated protein kinase (PKR). Inhibition of PKR prevented elevated CXCL8 production in astrocytes. We conclude that IL-1β and TNF-α, produced from HIV-1-infected and immune-competent macrophages, are critical in astrocyte CXCL8 production. Multiple protein kinases, including p38, JNK, ERK1/2, and PKR, participate in the inflammatory response of astrocytes. These observations will help to identify effective therapeutic strategies to reduce high-levels of CXCL8-mediated CNS inflammation during HAD.
KW - Astrocyte
KW - CXCL8
KW - HIV-1 associated dementia
KW - Inflammation
KW - Macrophage
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UR - http://www.scopus.com/inward/citedby.url?scp=49849084594&partnerID=8YFLogxK
U2 - 10.1016/j.jneuroim.2008.06.015
DO - 10.1016/j.jneuroim.2008.06.015
M3 - Article
C2 - 18653246
AN - SCOPUS:49849084594
VL - 200
SP - 100
EP - 110
JO - Advances in Neuroimmunology
JF - Advances in Neuroimmunology
SN - 0165-5728
IS - 1-2
ER -