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

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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The immunomodulatory effects of THP are exerted by a TLR4-dependent mech...
The immunomodulatory effects of THP are exerted by a TLR4-dependent mechanism. Bone marrow–derived murine macrophages (BM-Mo) (A) or murine splenocytes (B) from C57BL/6 WT, TLR2, TLR4, TLR9, or Myd88 KO mice were stimulated with THP, LPS, or Pam3Cys. Cell-free supernatants were collected 18 hours after addition of LPS, THP, or Pam3Cys and analyzed for TNF-α by ELISA. nd, not determined. *Significantly different from the values for activated controls in WT mice; P < 0.001. (C) Analysis of in vivo cytokine production in serum of C57BL/6 mice or TLR4 KO mice after i.v. administration of LPS or THP. One-hour postinjection serum levels of TNF-α were analyzed by ELISA. bd, below detection limit. Similar results were obtained in another independent experiment. (D) THP was injected i.v. on days 0, 1, 2, and 7 into C57BL/6 mice or TLR4 KO mice, and the subsequent THP-specific Ab response (IgG) was determined by ELISA. Ab response is shown at a serum dilution of 1:500.