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.