Department of Internal Medicine, Division of Infectious Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
PLoS One. 2013 Aug 14;8(8):e72488. doi: 10.1371/journal.pone.0072488. eCollection 2013.
Human monocytes/macrophages (M/M(Ф)) of the innate immunity sense and respond to microbial products via specific receptor coupling with stimulatory (such as TLR) and inhibitory (such as Tim-3) receptors. Current models imply that Tim-3 expression on M/M(Ø) can deliver negative signaling to TLR-mediated IL-12 expression through trans association with its ligand Galectin-9 (Gal-9) presented by other cells. However, Gal-9 is also expressed within M/M(Ø), and the effect of intracellular Gal-9 on Tim-3 activities and inflammatory responses in the same M/M(Ø) remains unknown. In this study, our data suggest that Tim-3 and IL-12/IL-23 gene transcriptions are regulated by enhanced or silenced Gal-9 expression within monocytes through synergizing with TLR signaling. Additionally, TLR activation facilitates Gal-9/Tim-3 cis association within the same M/M(Ø) to differentially regulate IL-12/IL-23 expressions through STAT-3 phosphorylation. These results reveal a ligand (Gal-9) compartment-dependent regulatory effect on receptor (Tim-3) activities and inflammatory responses via TLR pathways--a novel mechanism underlying cellular responses to external or internal cues.
人类先天免疫的单核细胞/巨噬细胞（M/M(Ø)）通过与刺激（如 TLR）和抑制（如 Tim-3）受体特异性偶联来感知和响应微生物产物。目前的模型表明，M/M(Ø)上的 Tim-3 表达可以通过与其配体 Galectin-9（Gal-9）的跨关联，向 TLR 介导的 IL-12 表达传递负信号，Gal-9 由其他细胞呈递。然而，Gal-9 也在 M/M(Ø) 内表达，细胞内 Gal-9 对同一 M/M(Ø)中 Tim-3 活性和炎症反应的影响尚不清楚。在这项研究中，我们的数据表明，通过与 TLR 信号协同作用，增强或沉默单核细胞内的 Gal-9 表达可以调节 Tim-3 和 IL-12/IL-23 基因转录。此外，TLR 激活促进同一 M/M(Ø)内 Gal-9/Tim-3 的顺式关联，通过 STAT-3 磷酸化差异调节 IL-12/IL-23 的表达。这些结果揭示了配体（Gal-9）区室依赖性对通过 TLR 途径的受体（Tim-3）活性和炎症反应的调节作用——这是细胞对外界或内部信号做出反应的一种新机制。
