Extracellular human T‐cell lymphotropic virus type I tax protein induces cytokine production in adult human microglial cells

Abstract

Tropical spastic paraparesis (HAM/TSP) is caused by human T-cell lymphotropic virus type I (HTLV-I) infection. Although the virus infects T cells in vivo and is capable of infecting microglia in vitro, the inflammatory demyelination has not been linked to virus in central nervous system tissue. Thus, indirect mechanisms (e.g., cytokines) could be involved in demyelination and inflammation. The ability of HTLV-I Tax protein to induce tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 in primary adult human microglia and peripheral blood macrophages (PBMs) was examined by enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction (RT-PCR). Tax (20 ng/ml) induced TNF-alpha in microglia (from undetectable or 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 stimulation. 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 (< or = 26 pg/ml). 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 beta = 3.6-fold). Thus, in HAM/TSP, extracellular Tax released from infiltrating T cells could induce cytokine release by microglia and contribute to demyelination and inflammation in the absence of detectable virus.

Human T cell leukemia virus type I and neurologic disease: Events in bone marrow, peripheral blood, and central nervous system during normal immune surveillance and neuroinflammation

“…Indeed, accumulating evidence suggests that extracellular Tax can act by binding to an unknown cell surface receptor(s) on target cells, and induce expression of a number of proin¯ammatory cytokines. Extracellular Tax has been shown to induce the production of interleukin-1b (IL-1b), IL-6, tumor necrosis factor-a (TNF-a) in macrophages, and microglial cells in a dose-dependent manner (Dhib-Jalbut et al, 1994). Additional studies will be required to determine the mechanism of extracellular Tax-mediated cytokine expression.…”

“…Recent studies have shown that Tax may be released from an infected cell and act as an extracellular cytokine on neighboring cells in the CNS. Extracellular Tax has been shown to induce NF-kB nuclear localization, and the expression of the immunoglobulin k light chain, IL-2Ra, IL-1b, IL-6, TNF-a, and TNF-b Lindholm et al, 1992;Marriott et al, 1992;Dhib-Jalbut et al, 1994). Possible mechanisms responsible for the cytokinelike effects of Tax may include extracellular Tax inducing a signaling cascade by binding to a speci®c cell surface receptor, or by the internalization and nuclear localization of extracellular Tax.…”

Immunocytochemical localization of the endogenous neuroexcitotoxin quinolinate in human peripheral blood monocytes/macrophages and the effect of human T-cell lymphotropic virus type I infection.

“…4). We found that Quin-IR in the controls also increased to some extent over (35)(36)(37). Quin has been reported to be increased in the CSF in response to other viral infections including HIV-1 and SIV (8)(9)(10); however, the cellular origin of Quin is unclear.…”

“…Based on biochemical studies, MOs have been hypothesized to be a potential source of Quin (11,38). In preliminary studies, we found that Quin-IR MOs/microglia were detectable in rat brain parenchyma after intracerebral injection of lipopolysaccharide (15) (37,41,42). IFN-y increased Quin-IR from -4% to 20%, but HTLV-I increased Quin-IR from -4% to 40%.…”

Human T cell lymphotropic virus type I genomic expression and impact on intracellular signaling pathways during neurodegenerative disease and leukemia

“…Prolonged treatment with Tax resulted in Tax-dependent cell death (300). Similarly, Dhib-Jalbut et al demonstrated that extracellular Tax also induced TNF-alpha and IL-6 expression in primary adult human microglia and peripheral blood macrophages (182). Therefore, circulating extracellular Tax in CNS, which either diffuses into the CNS from peripheral blood or secreted by CD4 + T cells, infiltrating the CNS can upregulate inflammatory cytokine expression resulting in neural degeneration in TSP patients in absence of detectable amount of the HTLV-I virus (269).…”