HIV-1-infected and/or immune-activated macrophages regulate astrocyte CXCL8 production through IL-1beta and TNF-alpha: involvement of mitogen-activated protein kinases and protein kinase R.
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-1beta and TNF-alpha 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-1beta or TNF-alpha treatment activated double-stranded RNA-activated protein kinase (PKR). Inhibition of PKR prevented elevated CXCL8 production in astrocytes. We conclude that IL-1beta and TNF-alpha, 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.
Zheng
Jialin C
JC
Department of Neurology & Institute of Neurology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. jzheng@unmc.edu
Huang
Yunlong
Y
Tang
Kang
K
Cui
Min
M
Niemann
Doug
D
Lopez
Alicia
A
Morgello
Susan
S
Chen
Shengdi
S
D000328:Adult; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005333:Fetus / Q000033:anatomy & histology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D016209:Interleukin-8 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C508606:CXCL8 protein, human; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D016209:Interleukin-8; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D020928:Mitogen-Activated Protein Kinases