GM-CSF and M-CSF modulate beta-chemokine and HIV-1 expression in microglia.
Significant numbers of patients with acquired immunodeficiency syndrome (AIDS) develop CNS infection primarily in macrophages and microglial cells. Therefore, the regulation of human immunodeficiency virus type 1 (HIV-1) infection and activation of the brain mononuclear phagocytes subsequent to infection are important areas of investigation. In the current report, we studied the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) in the expression of antiviral beta-chemokines and HIV-1 p24 in cultures of primary human fetal microglia. We found that stimulation with GM-CSF or M-CSF induced macrophage inflammatory proteins (MIP-1alpha and MIP-1beta) and augmented RANTES expression, after HIV-1 infection of microglia. This was not due to the effect of GM-CSF on viral expression because GM-CSF was neither necessary nor stimulatory for viral infection, nor did GM-CSF enhance the expression of env-pseudotyped reporter viruses. Blocking GM-CSF-induced microglial proliferation by nocodazole had no effect on beta-chemokine or p24 expression. The functional significance of the GM-CSF-induced beta-chemokines was suggested by the finding that, in the presence of GM-CSF, exogenous beta-chemokines lost their anti-HIV-1 effects. We further show that although HIV-1-infected microglia produced M-CSF, they failed to produce GM-CSF. In vivo, GM-CSF expression was localized to activated astrocytes and some inflammatory cells in HIV-1 encephalitis, suggesting paracrine activation of microglia through GM-CSF. Our results demonstrate a complex interplay between CSFs, chemokines, and virus in microglial cells and may have bearing on the interpretation of data derived in vivo and in vitro.
Si
Qiusheng
Q
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Cosenza
Melissa
M
Zhao
Meng-Liang
ML
Goldstein
Harris
H
Lee
Sunhee C
SC
D015526:AIDS Dementia Complex / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D001921:Brain / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism; D019742:Chemokines, CC / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000494:pharmacology; D016655:HIV Core Protein p24 / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000276:immunology / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D011247:Pregnancy; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D016655:HIV Core Protein p24; D019402:Macrophage Inflammatory Proteins; D011993:Recombinant Fusion Proteins; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor