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Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4–dependent mechanism
Marcus D. Säemann, … , Walter H. Hörl, Gerhard J. Zlabinger
Marcus D. Säemann, … , Walter H. Hörl, Gerhard J. Zlabinger
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):468-475. https://doi.org/10.1172/JCI22720.
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Article Immunology Article has an altmetric score of 1

Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4–dependent mechanism

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Abstract

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-κB. 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-α 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.

Authors

Marcus D. Säemann, Thomas Weichhart, Maximilian Zeyda, Günther Staffler, Michael Schunn, Karl M. Stuhlmeier, Yuri Sobanov, Thomas M. Stulnig, Shizuo Akira, Alexander von Gabain, Uwe von Ahsen, Walter H. Hörl, Gerhard J. Zlabinger

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Figure 2

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DC maturation induced by THP is not due to LPS or protein contamination....
DC maturation induced by THP is not due to LPS or protein contamination. (A) THP and LPS were left untreated or pretreated with polymyxin B (PMB) for 2 hours and then added to human immature DCs. After 48 hours, cells were harvested and analyzed by FACS. Profiles with fine lines represent staining patterns with an isotype-matched control Ab, and profiles with bold lines represent staining with a mAb of the indicated specificity. Data are representative of 5 independent experiments. (B) THP was incubated with PMB beads overnight. The supernatant was analyzed for the presence of THP by SDS-PAGE. Additionally, THP was incubated with proteinase K (Prot.K) for 45 minutes as described (11). The PMB-purified and the proteinase-treated samples were incubated with RAW 264.7 macrophages for 18 hours and analyzed for TNF-α. LPS as a control was treated similarly. Similar results were obtained in another independent experiment. (C) Effect of THP and LPS on the induction of TF activity in HUVECs. HUVECs were pretreated with or without IFN-γ and then exposed to THP or LPS. A 1-stage clotting assay was used to determine TF activity. The results are representative of 3 independent experiments. (D) LPS, Pam3Cys (P3C), THP isolated by standard NaCl precipitation (THP), THP isolated by NaCl precipitation and ultracentrifugation (THP-UC), and THP isolated by NaCl precipitation, ultracentrifugation, and diatomaceous earth filter (THP-DEF) were added to C57BL/6 splenocytes for 20 hours. Cell-free supernatants were analyzed for TNF-α by ELISA.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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