Hsu Yu-Lin, Wang Mei-Yi, Ho Ling-Jun, Huang Chuan-Yueh, Lai Jenn-Haung
Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.
J Cell Mol Med. 2015 May;19(5):1065-76. doi: 10.1111/jcmm.12500. Epub 2015 Mar 6.
Galectin-9 (Gal-9) exerts immunosuppressive effects by inducing apoptosis in T cells that produce interferon-γ and interleukin (IL)-17. However, Gal-9 can be pro-inflammatory in lipopolysaccharide-stimulated monocytes. Using microarray analysis, we observed that Gal-9 was up-regulated in human dendritic cells (DCs) after dengue virus (DV) infection. The investigation into the immunomodulatory effects and mechanisms of Gal-9 in DCs exposed to DV revealed that DV infection specifically increased mRNA and protein levels of Gal-9 but not those of Gal-1 or Gal-3. Blocking p38, but not c-Jun N-terminal kinase or extracellular signal-regulated kinase (ERK), inhibited DV-induced expression of Gal-9. Reduction in Gal-9 by small interference RNA treatment suppressed DV-stimulated migration of DCs towards the chemoattractants CCL19 and CCL21. In addition, DV-induced IL-12p40 production was reduced after knockdown of Gal-9 in DCs. Furthermore, Gal-9 deficiency suppressed DV-induced activation of nuclear factor-κB. Inhibition of DV-induced DC migration under conditions of Gal-9 deficiency was mediated through suppressing ERK activation but not by regulating the expression of CCR7, the receptor for CCL19 and CCL21. Both the reduction in IL-12 production and the suppression of ERK activity might account for the inhibition of DV-induced DC migration after knockdown of Gal-9. In summary, this study reveals the roles of Gal-9 in DV-induced migration of DCs. The findings indicate that Gal-9 might be a therapeutic target for preventing immunopathogenesis induced by DV infection.
半乳糖凝集素-9（Gal-9）通过诱导产生干扰素-γ和白细胞介素（IL）-17的T细胞凋亡发挥免疫抑制作用。然而，Gal-9在脂多糖刺激的单核细胞中可能具有促炎作用。通过微阵列分析，我们观察到登革病毒（DV）感染后人树突状细胞（DC）中Gal-9上调。对Gal-9在暴露于DV的DC中的免疫调节作用及其机制的研究表明，DV感染特异性增加了Gal-9的mRNA和蛋白质水平，但未增加Gal-1或Gal-3的水平。阻断p38而非c-Jun氨基末端激酶或细胞外信号调节激酶（ERK）可抑制DV诱导的Gal-9表达。通过小干扰RNA处理降低Gal-9可抑制DV刺激的DC向趋化因子CCL19和CCL21的迁移。此外，DC中Gal-9敲低后，DV诱导的IL-12p40产生减少。此外，Gal-9缺陷抑制了DV诱导的核因子-κB激活。Gal-9缺陷条件下对DV诱导的DC迁移的抑制是通过抑制ERK激活介导的，而不是通过调节CCL19和CCL21的受体CCR7的表达介导的。IL-12产生的减少和ERK活性的抑制都可能是Gal-9敲低后抑制DV诱导的DC迁移的原因。总之，本研究揭示了Gal-9在DV诱导的DC迁移中的作用。这些发现表明，Gal-9可能是预防DV感染诱导的免疫病理发生的治疗靶点。
