Division of Immunology, National Institute of Cholera and Enteric Diseases, Kolkata 700 010, India.
J Biol Chem. 2011 Oct 7;286(40):34542-51. doi: 10.1074/jbc.M111.241851. Epub 2011 Aug 16.
Vibrio cholerae hemolysin (HlyA) displays bipartite property while supervising macrophages (MΦ). The pore-forming toxin causes profound apoptosis within 3 h of exposure and in parallel supports activation of the defying MΦ. HlyA-induced apoptosis of MΦ remains steady for 24 h, is Toll-like receptor (TLR)-independent, and is driven by caspase-9 and caspase-7, thus involving the mitochondrial or intrinsic pathway. Cell activation is carried forward by time dependent up-regulation of varying TLRs. The promiscuous TLR association of HlyA prompted investigation, which revealed the β-prism lectin domain of HlyA simulated TLR4 up-regulation by jacalin, a plant lectin homologue besides expressing CD86 and type I cytokines TNF-α and IL-12. However, HlyA cytolytic protein domain up-regulated TLR2, which controlled CD40 for continuity of cell activation. Expression of TOLLIP before TLR2 and TLR6 abrogated TLR4, CD40, and CD86. We show that the transient expression of TOLLIP leading to curbing of activation-associated capabilities is a plausible feedback mechanism of MΦ to deploy TLR2 and prolong activation involving CD40 to encounter the HlyA cytolysin domain.
霍乱弧菌溶血素 (HlyA) 在调控巨噬细胞 (MΦ) 时表现出二部分特性。这种形成孔的毒素在暴露 3 小时内导致深刻的细胞凋亡，同时支持挑衅巨噬细胞的激活。HlyA 诱导的 MΦ 凋亡在 24 小时内保持稳定，不依赖 Toll 样受体 (TLR)，并由半胱天冬酶-9 和半胱天冬酶-7 驱动，因此涉及线粒体或内在途径。细胞激活通过时间依赖性上调不同的 TLR 来进行。HlyA 与 TLR 的广泛关联促使我们进行了研究，结果表明 HlyA 的 β-棱柱凝集素结构域模拟了 TLR4 的上调，这种模拟作用是由植物凝集素同源物 jacalin 引发的，除了表达 CD86 和 I 型细胞因子 TNF-α和 IL-12 之外。然而，HlyA 的细胞溶解蛋白结构域上调了 TLR2，控制了细胞激活的连续性 CD40。在 TLR2 和 TLR6 之前表达 TOLLIP 会阻断 TLR4、CD40 和 CD86。我们表明，TOLLIP 的瞬时表达导致激活相关能力的抑制是 MΦ 用来部署 TLR2 并延长激活涉及 CD40 以应对 HlyA 细胞溶解蛋白结构域的合理反馈机制。
