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

J Clin Invest. 2005 Feb;115(2):468-75. doi: 10.1172/JCI22720.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / pathology
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dendritic Cells / immunology*
  • Dendritic Cells / pathology
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Inflammation / immunology
  • Inflammation / pathology
  • Kidney / immunology
  • Kidney / microbiology
  • Kidney / pathology
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / pathology
  • Mice
  • Mice, Knockout
  • Mucoproteins / immunology*
  • NF-kappa B / immunology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Receptors, Cell Surface / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • Tumor Necrosis Factor-alpha / immunology
  • Urinary Tract Infections / immunology*
  • Urinary Tract Infections / microbiology
  • Urinary Tract Infections / pathology
  • Uromodulin

Substances

  • DNA-Binding Proteins
  • Mucoproteins
  • NF-kappa B
  • Receptors, Cell Surface
  • TLR9 protein, human
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • Tumor Necrosis Factor-alpha
  • UMOD protein, human
  • Umod protein, mouse
  • Uromodulin