Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Research Institute, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
J Leukoc Biol. 2017 Sep;102(3):925-939. doi: 10.1189/jlb.4A0716-332RR. Epub 2017 Jul 11.
Monocyte-derived Mϕs (MDMs) from HIV-infected patients and MDM infected in vitro with HIV exhibit a reduced ability to secrete various cytokines, including IL-12. Recently, IL-27, an IL-12 family cytokine, was shown to inhibit HIV replication in Mϕ. Whether HIV infection or HIV accessory protein(s) impact IL-27 production in Mϕs remains unknown. Herein, we show that in vitro HIV infection, as well as intracellular HIV-Tat (Tat) and Tat peptides, inhibit LPS-induced IL-27 production in human MDMs, suggesting impairment of the TLR4 signaling pathway. To understand the signaling pathways governing HIV or Tat-mediated inhibition of LPS-induced IL-27 production, we first demonstrated that p38 MAPK, PI3K, Src-homology region 2 domain-containing tyrosine phosphatase 1 (SHP-1), and Src kinases regulate LPS-induced IL-27 production in MDMs. Tat caused down-regulation of TNFR-associated factor (TRAF)-6 and inhibitor of apoptosis 1 (cIAP-1) and subsequently decreased phosphorylation of downstream PI3K and p38 MAPKs, which were implicated in LPS-induced IL-27 production. Whereas SHP-1 and Src kinases regulated LPS-induced IL-27 production, Tat did not inhibit these kinases, suggesting that they were not involved in Tat-mediated inhibition of LPS-induced IL-27 production. In contrast to Tat, in vitro HIV infection of MDM inhibited LPS-induced IL-27 production via inhibition of p38 MAPK activation. Overall, HIV and Tat inhibit LPS-induced IL-27 production in human macrophages via distinct mechanisms: Tat through the inhibition of cIAP-1-TRAF-6 and subsequent inhibition of PI3K and p38 MAPKs, whereas HIV through the inhibition of p38 MAPK activation.
单核细胞衍生的巨噬细胞（MDMs）来源于 HIV 感染的患者，并且在体外感染 HIV 的 MDM 表现出分泌各种细胞因子（包括 IL-12）的能力降低。最近，IL-27，一种 IL-12 家族细胞因子，被证明可以抑制巨噬细胞中的 HIV 复制。HIV 感染或 HIV 辅助蛋白是否会影响巨噬细胞中 IL-27 的产生尚不清楚。在此，我们表明，体外 HIV 感染以及细胞内 HIV-Tat（Tat）和 Tat 肽抑制了人 MDMs 中 LPS 诱导的 IL-27 产生，表明 TLR4 信号通路受损。为了了解调控 HIV 或 Tat 介导的 LPS 诱导的 IL-27 产生抑制的信号通路，我们首先证明了 p38 MAPK、PI3K、Src 同源性区域 2 结构域包含的酪氨酸磷酸酶 1（SHP-1）和Src 激酶调节 MDMs 中 LPS 诱导的 IL-27 产生。Tat 导致肿瘤坏死因子受体相关因子（TRAF）-6 和凋亡抑制剂 1（cIAP-1）的下调，随后降低了下游 PI3K 和 p38 MAPK 的磷酸化，这些磷酸化在 LPS 诱导的 IL-27 产生中起作用。尽管 SHP-1 和 Src 激酶调节 LPS 诱导的 IL-27 产生，但 Tat 并没有抑制这些激酶，这表明它们不参与 Tat 介导的 LPS 诱导的 IL-27 产生抑制。与 Tat 相反，MDM 的体外 HIV 感染通过抑制 p38 MAPK 激活来抑制 LPS 诱导的 IL-27 产生。总体而言，HIV 和 Tat 通过不同的机制抑制人巨噬细胞中 LPS 诱导的 IL-27 产生：Tat 通过抑制 cIAP-1-TRAF-6 以及随后抑制 PI3K 和 p38 MAPK，而 HIV 通过抑制 p38 MAPK 激活。
