Abstract
BackgroundIn HIV-1 infected patients, production of interleukin-10 (IL-10), a highly immunosuppressive cytokine, is associated with progression of infection toward AIDS. HIV-1 Tat protein, by interacting with TLR4-MD2 at the membrane level, induces IL-10 production by primary human monocytes and macrophages. In the present study we evaluated the effect of the TLR4 antagonist Eritoran tetrasodium (E5564) on HIV-1 Tat-induced IL-10 production.FindingsHere, we confirm that the recombinant HIV-1 Tat protein and the GST-Tat 1–45 fusion protein efficiently stimulate IL-10 production by primary monocytes and macrophages and that this stimulation is inhibited by blocking anti-TLR4 mAbs. We show that a similar inhibition is observed by preincubating the cells with the TLR4 antagonist E5564.ConclusionThis study provides compelling data showing for the first time that the TLR4 antagonist E5564 inhibits the immunosuppressive cytokine IL-10 production by primary human monocytes and macrophages incubated in the presence of HIV-1 Tat protein.
Highlights
In HIV-1 infected patients, the deregulation of the immune system precedes the decline of the T CD4+ lymphocytes population
Recombinant HIV-1 Tat protein 1–86 or recombinant Glutathione S-transferase (GST)-Tat 1–45 produced from our laboratory as previously described [21] and controlled for endotoxin contamination using the Limulus amebocyte lysate (LAL) assay (Bio-Sepra, France) [10,21,22,23] were added to primary human monocytes pre-incubated or not of with the HTA125 anti-TLR4 mAb or with a nonspecific isotype-matched IgG (1 μg/ml)
We showed that stimulation with recombinant Tat protein or recombinant GST-Tat 1–45 stimulated IL-10 production (Figure 2)
Summary
In HIV-1 infected patients, the deregulation of the immune system precedes the decline of the T CD4+ lymphocytes population. Non-adherent cells were removed, the remaining cells were washed twice and stimulated by increasing concentrations of LPS either directly or after preincubation with 1 μg/ml HTA125 anti-TLR4 blocking monoclonal antibody (mAb) (eBioscience), or with 10 nM placebo or with 10 nM E5564 (placebo and E5564 were kindly provided by Eisai Research Institute of Boston). Used at these concentrations E5564 and placebo displayed no cytotoxic effect (data not shown) [20]. We determined in vitro effects of the HIV-1 Tat protein on IL-10 production by human monocytes
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