PDGF synergistically enhances IFN-gamma-induced expression of CXCL10 in blood-derived macrophages: implications for HIV dementia.
There is increasing cumulative evidence that activated mononuclear phagocytes (macrophages/microglia) releasing inflammatory mediators in the CNS are a better correlate of HIV-associated dementia (HAD) than the actual viral load in the brain. Earlier studies on simian HIV/rhesus macaque model of NeuroAIDS confirmed that pathological changes in brains of macaques with encephalitis were associated with up-regulation of platelet-derived growth factor (PDGF) and the chemokine, CXCL10. Because the complex interplay of inflammatory mediators released by macrophages often leads to the induction of neurotoxins in HAD, we hypothesized that PDGF could interact with IFN-gamma to modulate the expression of CXCL10 in these primary virus target cells. Although PDGF alone had no effect on the induction of CXCL10 in human macrophages, in conjunction with IFN-gamma, it significantly augmented the expression of CXCL10 RNA & protein through transcriptional and posttranscriptional mechanisms. Signaling molecules, such as JAK and STATs, PI3K, MAPK, and NF-kappaB were found to play a role in the synergistic induction of CXCL10. Furthermore, PDGF via its activation of p38 MAPK was able to increase the stability of IFN-gamma-induced CXCL10 mRNA. Understanding the mechanisms involved in the synergistic up-regulation of CXCL10 could aid in the development of therapeutic modalities for HAD.
Dhillon
Navneet Kaur
NK
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Peng
Fuwang
F
Ransohoff
Richard M
RM
Buch
Shilpa
S
D015526:AIDS Dementia Complex / Q000276:immunology*; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction
C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D016328:NF-kappa B; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases; D020929:Mitogen-Activated Protein Kinase Kinases