Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism.
Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism.
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DOI：
10.1172/jci22720
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发表时间：
2005-02
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通讯作者：
M. Säemann;T. Weichhart;M. Zeyda;G. Staffler;Michael Schunn;K. Stuhlmeier;Y. Sobanov;T. Stulnig;S. Akira;A. von Gabain;U. von Ahsen;W. Hörl;G. Zlabinger
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作者：
M. Säemann;T. Weichhart;M. Zeyda;G. Staffler;Michael Schunn;K. Stuhlmeier;Y. Sobanov;T. Stulnig;S. Akira;A. von Gabain;U. von Ahsen;W. Hörl;G. Zlabinger
Tamm-Horsfall糖蛋白（THP）仅在肾脏中表达，并构成哺乳动物尿液中最丰富的蛋白质。THP在抗菌宿主防御和泌尿生殖道炎症性疾病中的关键作用已被提出。我们证明THP通过Toll样受体-4（TLR 4）激活髓样DC以获得完全成熟的DC表型。THP触发典型的TLR信号传导，最终激活NF-κ B。与TLR 2和TLR 9缺陷小鼠相比，TLR 4和MyD 88缺陷小鼠的骨髓源性巨噬细胞对THP无反应。体内THP驱动的TNF-α产生在WT中是明显的，但在Tlr 4-/-小鼠中不是。重要的是，在Tlr 4-/-小鼠中，在尿路炎症中始终可检测到的THP特异性Ab的产生完全钝化。这些数据表明，THP是先天性和获得性免疫的调节因子，因此可能对尿路中的宿主免疫具有显著影响。
Tamm-Horsfall glycoprotein (THP) is expressed exclusively in the kidney and constitutes the most abundant protein in mammalian urine. A critical role for THP in antibacterial host defense and inflammatory disorders of the urogenital tract has been suggested. We demonstrate that THP activates myeloid DCs via Toll-like receptor-4 (TLR4) to acquire a fully mature DC phenotype. THP triggers typical TLR signaling, culminating in activation of NF-kappaB. Bone marrow-derived macrophages from TLR4- and MyD88-deficient mice were nonresponsive to THP in contrast to those from TLR2- and TLR9-deficient mice. In vivo THP-driven TNF-alpha production was evident in WT but not in Tlr4-/- mice. Importantly, generation of THP-specific Abs consistently detectable in urinary tract inflammation was completely blunted in Tlr4-/- mice. These data show that THP is a regulatory factor of innate and adaptive immunity and therefore could have significant impact on host immunity in the urinary tract.