Abstract
HIV-1 Tat protein induces the production of CXCL8 chemokine in a TLR4/MD2 and PKC dependent manner. The objective of this study was to understand whether these two pathways were distinct or constituted a single common pathway, and to determine the nature of the PKC isoforms involved and their interrelation with the activation of NF-κB and CXCL8 gene product expression. Here, we show that Tat-induced CXCL8 production is essentially dependent on the activation of PKC delta isoform, as shown a) by the capacity of PKC delta dominant negative (DN), and Rottlerin, a selective PKC delta pharmacological inhibitor, to inhibit Tat-induced CXCL8 production and b) by the ability of the constitutively active (CAT) isoform of PKC delta to induce CXCL8 production in a HEK cell line in the absence of Tat stimulation. The finding that comparable amounts of CXCL8 were produced following stimulation with either Tat protein, PKC-delta CAT transfection, or both, argue for the implication of one common pathway where PKC delta is activated downstream of TLR4 recruitment and leads to the activation of NF-κB. Altogether, our results underline the crucial role of PKC delta isoform in activating gene expression of CXCL8, a cytokine largely implicated in the physiopathology of HIV-1 infection.
Highlights
Human Immunodeficiency Virus type-1 (HIV-1) infection is associated with large and continuous production of pro-inflammatory cytokines/chemokines including TNF-α, IL-1β, IFN-α, IL-6, and CXCL8[1,2,3,4,5,6,7]
In line with our previous study[50], we demonstrated that the HEK 293 cell line, transfected with TLR4 in association with its cofactors, CD14 and MD2 (HEK-CD14-MD2-TLR4) produced CXCL8 cytokine following treatment with HIV-1 Tat protein, whereas cells transfected with the empty vector, HEK-null did not, demonstrating that the production of CXCL8 cytokine is dependent on the activation of TLR4MD2-CD14 by HIV-1 Tat protein (Fig. 1A)
We showed that Tat protein induced CXCL8 production in primary human monocytes derived dendritic cells which could be inhibited by TLR4 antagonist, using LPS-RS (Fig. 1B)
Summary
Human Immunodeficiency Virus type-1 (HIV-1) infection is associated with large and continuous production of pro-inflammatory cytokines/chemokines including TNF-α, IL-1β, IFN-α, IL-6, and CXCL8 (previously named IL-8)[1,2,3,4,5,6,7]. In addition to LPS, relatively high levels of other microbial products, such as lipoteichoic acid (LTA), and bacterial DNA, are found to be present in the blood and in other compartments, such as the peripheral lymph nodes and liver These translocated bacterial PAMPs (Pathogen Associated Molecular Patterns) seem to act more strongly and continuously as a secondary stimulation signal, maintaining a persistent chronic immune activation and inflammatory state by activating various PRR such as TLR4 by LPS, TLR2 by LTA and TLR9 by DNA, in various organ tissues[23]. We focused on understanding the molecular signalling pathway activated by Tat protein to induce CXCL8
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