Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism.
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.
Säemann
Marcus D
MD
Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria.
Weichhart
Thomas
T
Zeyda
Maximilian
M
Staffler
Günther
G
Schunn
Michael
M
Stuhlmeier
Karl M
KM
Sobanov
Yuri
Y
Stulnig
Thomas M
TM
Akira
Shizuo
S
von Gabain
Alexander
A
von Ahsen
Uwe
U
Hörl
Walter H
WH
Zlabinger
Gerhard J
GJ
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007668:Kidney / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009088:Mucoproteins / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014552:Urinary Tract Infections / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D058949:Uromodulin
D004268:DNA-Binding Proteins; D009088:Mucoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C495371:TLR9 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; C548612:UMOD protein, human; C548613:Umod protein, mouse; D058949:Uromodulin