ABSTRACT
Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders. IDO expression is induced by IFN-gamma and leads to neurotoxicity by generating quinolinic acid. Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites. IL-4 and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-gamma in different cell types. Here, we investigated the effects of these cytokines on IDO expression in microglia. Interestingly, we observed that both IL-4 and IL-13 greatly enhanced IFN-gamma-induced IDO expression. However, tryptophanyl-tRNA synthetase (WRS), which is coinduced with IDO by IFN-gamma, is downregulated by IL-4 and IL-13. The effect of IL-4 and IL-13 was independent of STAT-6. Modulation of IDO but not WRS was eliminated by inhibition of protein phosphatase 2A (PP2A) activity. The phosphatidylinositol 3-kinase (PI3K) pathway further differentiated the regulation of these two enzymes, as inhibiting the PI3K pathway eliminated IFN-gamma induction of IDO, whereas such inhibition greatly enhanced WRS expression. These findings show discordance between modulations of expression of two distinct enzymes utilizing tryptophan as a common substrate, and raise the possibility of their involvement in regulating immune responses in various neurological disorders.
Subject(s)
Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Interferon-gamma/pharmacology , Interleukin-4/pharmacology , Microglia/drug effects , Microglia/metabolism , Tryptophan-tRNA Ligase/metabolism , Animals , Cells, Cultured , Gene Expression/drug effects , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Interleukin-13/pharmacology , Mice , Mice, Knockout , Phosphatidylinositol 3-Kinases/metabolism , Phosphoprotein Phosphatases/metabolism , Phosphorylation , Protein Phosphatase 2 , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , STAT1 Transcription Factor/physiology , STAT6 Transcription Factor/genetics , STAT6 Transcription Factor/physiology , Signal Transduction/physiology , Tryptophan-tRNA Ligase/geneticsABSTRACT
The virus/host interactions during the acute phase of human immunodeficiency virus (HIV) infection help determine the course of disease. During this time period, virus enters the brain. Here, we report clusters of genes whose transcripts are significantly upregulated in the frontal lobe of the brain during acute simian immunodeficiency virus (SIV) infection of rhesus monkeys. Many of these genes are involved in interferon (IFN) and/or interleukin (IL)-6 pathways. Although neither IFNalpha nor IFNgamma are elevated in the brain, IL6 is increased. Both IFNalpha and IL6 are elevated in plasma during this acute phase. The upregulation of STAT1, verified by immunohistochemical staining, can be due to both central nervous system (CNS) (SIV and IL6) and peripheral (IFNalpha and IL6) causes, and can itself drive the expression of many of these genes. Examination of the levels of expression of the upregulated genes in the post-acute and long-term phases of infection, as well as in SIV encephalitis, reveals increased expression throughout SIV infection, which may serve to protect the brain, but can have untoward long-term consequences.
Subject(s)
Brain/virology , Interferons/metabolism , Interleukin-6/metabolism , Simian Acquired Immunodeficiency Syndrome/metabolism , Simian Immunodeficiency Virus/physiology , Analysis of Variance , Animals , Brain/metabolism , DNA-Binding Proteins/metabolism , Disease Progression , Enzyme-Linked Immunosorbent Assay/methods , Humans , Immunohistochemistry/methods , Interferons/genetics , Interleukin-6/genetics , Macaca mulatta , Oligonucleotide Array Sequence Analysis/methods , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods , STAT1 Transcription Factor , Simian Acquired Immunodeficiency Syndrome/genetics , Simian Acquired Immunodeficiency Syndrome/virology , Time Factors , Trans-Activators/metabolism , Up-Regulation , Viral Load/methodsABSTRACT
The human immunodeficiency virus type 1-associated cognitive-motor disorder, including the AIDS dementia complex, is characterized by brain functional abnormalities that are associated with injury initiated by viral infection of the brain. Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in tryptophan catabolism in extrahepatic tissues, can lead to neurotoxicity through the generation of quinolinic acid and immunosuppression and can alter brain chemistry via depletion of tryptophan. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model of AIDS, we demonstrate that cells of the macrophage lineage are the main source for expression of IDO in the SIV-infected monkey brain. Animals with SIV encephalitis have the highest levels of IDO mRNA, and the level of IDO correlates with gamma interferon (IFN-gamma) and viral load levels. In vitro studies on mouse microglia reveal that IFN-gamma is the primary inducer of IDO expression. These findings demonstrate the link between IDO expression, IFN-gamma levels, and brain pathology signs observed in neuro-AIDS.
