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PDGF Synergistically Enhances IFN--Induced Expression of CXCL10 in Blood-Derived Macrophages: Implications for HIV Dementia¹

Navneet Kaur Dhillon^*, Fuwang Peng^*, Richard M. Ransohoff and Shilpa Buch^2,*

^* Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160; and Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195

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- 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-, 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-B 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--induced CXCL10 mRNA. Understanding the mechanisms involved in the synergistic up-regulation of CXCL10 could aid in the development of therapeutic modalities for HAD.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants DA020392-01, MH62969-01, RR016443, MH-068212, MH072355 (to S.B.), and NS32151 (to R.M.R.) from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Shilpa J. Buch, Department of Molecular and Integrative Physiology, 5000 Wahl Hall East, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. E-mail address: sbuch{at}kumc.edu

³ Abbreviations used in this paper: HAD, HIV-associated dementia; MDM, monocyte derived macrophages; SHIV, simian HIV; PDGF, platelet-derived growth factor; ISRE, IFN-stimulated response element; Act D, actinomycin D.