CD38 regulation in activated astrocytes: implications for neuroinflammation and HIV-1 brain infection.
Reactive astrogliosis is a key pathological aspect of neuroinflammatory disorders including human immunodeficiency virus type 1 (HIV-1)-associated neurological disease. On the basis of previous data that showedastrocytes activated with interleukin (IL)-1beta induce neuronal injury, we analyzed global gene changes in IL-1beta-activated human astrocytes by gene microarray. Among the up-regulated genes, CD38, a 45-kDa type II single chain transmembrane glycoprotein, was a top candidate, with a 17.24-fold change that was validated by real-time polymerase chain reaction. Key functions of CD38 include enzymatic activities and involvement in adhesion and cell signaling. Importantly, CD38(+)CD8(+) T-cell expression is a clinical correlate for progression of HIV-1 infection and biological marker for immune activation. Thus, CD38 expression in HIV-1 and/or IL-1beta-stimulated human astrocytes and human brain tissues was analyzed. IL-1beta and HIV-1 activation of astrocytes enhanced CD38 mRNA levels. Both CD38 immunoreactivity and adenosine 5'-diphosphate (ADP)-ribosyl cyclase activity were up-regulated in IL-1beta-activated astrocytes. CD38 knockdown using specific siRNAs significantly reduced astrocyte proinflammatory cytokine and chemokine production. However, CD38 mRNA levels were unchanged in IL-1beta knockdown conditions, suggesting that IL-1beta autocrine loop is not implicated in this process. Quantitative immunohistochemical analysis of HIV-seropositive without encephalitis and HIV-1 encephalitis brain tissues showed significant up-regulation of CD38, which colocalized with glial fibrillary acidic protein-positive cells in areas of inflammation. These results suggest an important role of CD38 in the regulation of astrocyte dysfunction during the neuroinflammatory processes involved in neurodegenerative/neuroinflammatory disorders such as HIV-1 encephalitis.
Kou
Wei
W
Department of Cell Biology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Banerjee
Sugato
S
Eudy
James
J
Smith
Lynette M
LM
Persidsky
Raisa
R
Borgmann
Kathleen
K
Wu
Li
L
Sakhuja
Namita
N
Deshpande
Muralidhar S
MS
Walseth
Timothy F
TF
Ghorpade
Anuja
A
D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology; D001921:Brain / Q000166:cytology / Q000473:pathology / Q000821:virology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018792:Encephalitis, Viral / Q000473:pathology*; D005333:Fetus; D020869:Gene Expression Profiling / Q000379:methods; D006679:HIV Seropositivity / Q000473:pathology; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012333:RNA, Messenger; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D053583:Interleukin-1beta; D016209:Interleukin-8; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D036563:Cyclic ADP-Ribose; D051997:ADP-ribosyl Cyclase 1; D020778:Matrix Metalloproteinase 2