EXTRACELLULAR HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE-I TAX PROTEIN INDUCES CYTOKINE PRODUCTION IN ADULT HUMAN MICROGLIAL CELLS

Tropical spastic paraparesis (HAM/TSP) is caused by human T-cell lymph otropic virus type I (HTLV-I) infection. Although the virus infects T cells in vivo and is capable of infecting microglia in vitro, the infl ammatory demyelination has not been linked to virus in central nervous system tissue. Thus, indirect mechanisms (e.g., cytokines) could be i nvolved in demyelination and inflammation. The ability of HTLV-I Tax p rotein to induce tumor necrosis factor-alpha (TNF-alpha), interleukin- 1 beta (IL-1 beta), and IL-6 in primary adult human microglia and peri pheral blood macrophages (PBMs) was examined by enzyme-linked immunoso rbent assay and reverse transcription-polymerase chain reaction (RT-PC R). Tax (20 ng/ml) induced TNF-alpha in microglia (from undetectable o r low basal levels to 215-1,075 pg/ml, mean 576 +/- 375 pg/ml, n = 4) and in PBMs (70-1,900, mean 646 +/- 844 pg/ml, n = 4). This induction was dose dependent, Tax specific, and maximal at 8 hours after stimula tion. IL-6 levels in microglia increased from a basal level of 368 +/- 194 to 664 +/- 270 pg/ml 24 hours after Tax stimulation. In contrast, IL-1 beta levels were modestly induced (less than or equal to 26 pg/m l). An increase in mRNA levels of the three cytokines was observed by semiquantitative RT-PCR (TNF-alpha = 28-fold; IL-6 = 5.6-fold; IL-1 be ta = 3.6-fold). Thus, in HAM/TSP, extracellular Tax released from infi ltrating T cells could induce cytokine release by microglia and contri bute to demyelination and inflammation in the absence of detectable vi rus.