Abstract
Tamm-Horsfall glycoprotein (THP) or uromodulin is produced by renal tubular cells of the ascending limp of Henle’s loop. Tamm-Horsfall glycoprotein is a 80-90KDa GPI-anchored protein and contains approximately 25-35% of carbohydrate-side chain in weight with abundant sialic acid. THP is an important defense molecule in protecting urinary tract epithelial cells from microbial invasion. Our previous data has shown that THP can bind to diverse proteins including immunoglobulin light chains, complement component 1q, interleukin-1(IL-1), and tumor necrosis factor-α (TNF-α).In addition, we found that THP could enhance PMN phagocytosis. However, the mechanism phagocytosis-enhancing activity of THP remained unclear. For further elucidating the mechanism for this activity by THP, we purified THP from normal human urine. At first, THP was cleaved by different carbohydrate-and protein-degrading enzymes and the data demonstrated that the protein-core structure was more important for activating PMN phagocytosis than carbohydrate-side chains. Next, we found that THP could bind to the surface membrane of PMN and induced phosphorylation of MAP kinase (p38),ERK1/2 and NF-кB signaling pathways. Furthermore, p38 inhibitor SB203580 could abolish LPS and THP induced-PMN phagocytosis. Finally, we found THP and EGF (Epidermal growth factor) exhibited a similar function on PMN and HL-60(human promyelocytic leukemia cells). Our results demonstrated that EGF and THP could induce PMN phagocytosis via rearrangement of cytoskeletal molecules by increasing expression of cdc42, RhoA and Rac. GW2974 (EGFR inhibitor) could reduce the THP- and EGF-induced PMN phagocytosis and ERK1/2 expression in HL-60. In contrast, GW2974 had no effect on LPS-induced PMN phagocytosis. Putting these results together, we concluded that THP used EGF-like domain to stimulate PMN via EGF singling pathway to phosphorylated p38 and ERK1/2. The EGF-like domain in THP molecule may play an important role in PMN phagocytosis-enhancing activity.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
