Ibudilast, a pharmacologic phosphodiesterase inhibitor, prevents human immunodeficiency virus-1 Tat-mediated activation of microglial cells.

ABSTRACT: Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorders (HAND) occur, in part, due to the inflammatory response to viral proteins, such as the HIV-1 transactivator of transcription (Tat), in the central nervous system (CNS). Given the need for novel adjunctive therapies for HAND, we hypothesized that ibudilast would inhibit Tat-induced excess production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF?) in microglial cells. Ibudilast is a non-selective cyclic AMP phosphodiesterase inhibitor that has recently shown promise as a treatment for neuropathic pain via its ability to attenuate glial cell activation. Accordingly, here we demonstrate that pre-treatment of both human and mouse microglial cells with increasing doses of ibudilast inhibited Tat-induced synthesis of TNF? by microglial cells in a manner dependent on serine/threonine protein phosphatase activity. Ibudilast had no effect on Tat-induced p38 MAP kinase activation, and blockade of adenosine A(2A) receptor activation did not reverse ibudilast's inhibition of Tat-induced TNF? production. Interestingly, ibudilast reduced Tat-mediated transcription of TNF?, via modulation of nuclear factor-kappa B (NF-?B) signaling, as shown by transcriptional activity of NF-?B and analysis of inhibitor of kappa B alpha (I?B?) stability. Together, our findings shed light on the mechanism of ibudilast's inhibition of Tat-induced TNF? production in microglial cells and may implicate ibudilast as a potential novel adjunctive therapy for the management of HAND.

SUBMITTER: Kiebala M 

PROVIDER: S-EPMC3072977 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature