Tamm-Horsfall Protein is a Potent Immunomodulatory Molecule and a Disease Biomarker in the Urinary System
Journal
Molecules (Basel, Switzerland)
Journal Volume
23
Journal Issue
1
Pages
200
Date Issued
2018-01-22
Author(s)
Abstract
Tamm-Horsfall protein (THP), or uromodulin (UMOD), is an 80-90-kDa phosphatidylinositol-anchored glycoprotein produced exclusively by the renal tubular cells in the thick ascending limb of the loop of Henle. Physiologically, THP is implicated in renal countercurrent gradient formation, sodium homeostasis, blood pressure regulation, and a defense molecule against infections in the urinary system. Investigations have also revealed that THP is an effective binding ligand for serum albumin, immunoglobulin G light chains, complement components C1 and C1q, interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and interferon-γ through its carbohydrate side chains for maintaining circulatory and renal immune homeostasis. Thus, THP can be regarded as part of the innate immune system. UMOD mutations play crucial roles in congenital urolithiasis, hereditary hyperuricemia/gout, and medullary cystic kidney diseases. Recent investigations have focused on the immunomodulatory effects of THP on immune cells and on THP as a disease biomarker of acute and chronic kidney diseases. Our studies have suggested that normal urinary THP, through its epidermal growth factor (EGF)-like domains, binds to the surface-expressed EGF-like receptors, cathepsin G, or lactoferrin to enhance polymorphonuclear leukocyte phagocytosis, proinflammatory cytokine production by monocytes/macrophages, and lymphocyte proliferation by activating the Rho family and mitogen-activated protein kinase signaling pathways. Furthermore, our data support both an intact protein core structure and carbohydrate side chains are important for the different protein-binding capacities of THP. Prospectively, parts of the whole THP molecule may be used for anti-TNF-α therapy in inflammatory diseases, autoantibody-depleting therapy in autoimmune disorders, and immune intensification in immunocompromised hosts.
Subjects
Tamm–Horsfall protein (THP); immunomodulation; polymorphonuclear leukocyte phagocytosis; protein-binding capacity; renal tubular biomarker
SDGs
Other Subjects
biological marker; immunologic factor; protein binding; Tamm Horsfall glycoprotein; animal; chemistry; gene expression; genetics; human; immunology; immunomodulation; kidney tubule; metabolism; neutrophil; phagocytosis; urinary tract disease; Animals; Biomarkers; Gene Expression; Humans; Immunologic Factors; Immunomodulation; Kidney Tubules; Neutrophils; Phagocytosis; Protein Binding; Urologic Diseases; Uromodulin
Publisher
MDPI AG
Type
review