Cytokine induction by the hepatitis B virus capsid in macrophages is facilitated by membrane heparan sulfate and involves TLR2
Cytokine induction by the hepatitis B virus capsid in macrophages is facilitated by membrane heparan sulfate and involves TLR2
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DOI：
10.4049/jimmunol.175.5.3165
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发表时间：
2005-09-01
影响因子：
4.4
通讯作者：
Shaul, Y
中科院分区：
文献类型：
--
作者：
Cooper, A;Tal, G;Shaul, Y
B型肝炎病毒（HBV）核心抗原（HBcAg）作为高免疫原性衣壳壳的结构亚基。HBcAg具有独特的富含丝氨酸的C末端，其与衣壳诱导的免疫应答有关。在这项研究中，我们研究了HBV衣壳在人THP-1巨噬细胞中诱导促炎性和调节性细胞因子的能力及其可能的潜在机制。全长HBc衣壳，而不是缺乏HBcAg的富含精氨酸的结构域的HBc-144衣壳，有效地结合分化的THP-1巨噬细胞并强烈诱导TNF-α、IL-6和IL-12 p40。衣壳与巨噬细胞的结合和细胞因子诱导独立于与富含精氨酸的结构域相关的RNA。可溶性肝素和硫酸乙酰肝素，而不是硫酸软骨素，通过抑制衣壳结合THP-1巨噬细胞，大大减少细胞因子诱导。此外，富含丝氨酸的结构域中的丝氨酸磷酸化调节衣壳与巨噬细胞的结合和细胞因子反应。衣壳对细胞因子的诱导涉及NF-κ B、ERK-1/2和p38 MAPK的激活，并且不需要内体酸化。最后，NF-κ B在HEK 293细胞中被衣壳激活，特别需要TLR 2的表达，并且被可溶性肝素损害。因此，巨噬细胞中HBV衣壳的细胞因子诱导是通过其富含丝氨酸的结构域与膜硫酸乙酰肝素的相互作用来促进的，并且涉及通过TLR 2的信号传导。
The hepatitis B virus (HBV) core Ag (HBcAg) serves as the structural subunit of the highly immunogenic capsid shell. HBcAg harbors a unique arginine-rich C terminus that was implicated in immune responses induced by the capsid. In this study, we examined the capacity of the HBV capsid to induce proinfiammatory and regulatory cytokines in human THP-1 macrophages and the possible underlying mechanism. Full-length HBc capsids, but not HBc-144 capsids lacking the arginine-rich domain of HBcAg, efficiently bound differentiated THP-1 macrophages and strongly induced TNF-alpha, IL-6, and IL-12p40. Capsid binding to macrophages and cytokine induction were independent of the RNA associated with the arginine-rich domain. Soluble heparin and heparan sulfate but not chondroitin sulfates greatly diminished cytokine induction through inhibition of capsid binding to THP-1 macrophages. Furthermore, serine phosphorylation in the arginine-rich domain modulates capsid binding to macrophages and the cytokine response. Induction of cytokines by the capsid involved activation of NF-kappa B, ERK-1/2, and p38 MAPK and did not require endosomal acidification. Finally, NF-kappa B activation by the capsid in HEK 293 cells specifically required expression of TLR2 and was compromised by soluble heparin. Thus, cytokine induction by the HBV capsid in macrophages is facilitated by interaction of its arginine-rich domain with membrane heparan sulfate and involves signaling through TLR2.