EGF Receptor-Dependent Mechanism May be Involved in the Tamm–Horsfall Glycoprotein-Enhanced PMN Phagocytosis via Activating Rho Family and MAPK Signaling Pathway

Abstract

Abstract:Our previous studies showed that urinary Tamm-Horsfall glycoprotein (THP) potently enhanced polymorphonuclear neutrophil (PMN) phagocytosis. However, the domain structure(s), signaling pathway and the intracellular events responsible for THP-enhanced PMN phagocytosis remain to be elucidated. THP was purified from normal human urine. The human promyelocytic leukemia cell line HL-60 was induced to differentiate into PMNs by all-trans retinoid acid. Pretreatment with different MAPK and PI3K inhibitors was used to delineate signaling pathways in THP-enhanced PMN phagocytosis. Phosphorylation of molecules responsible for PMN phagocytosis induced by OPEN ACCESSMolecules 2014, 19 1329 bacterial lipopolysaccharide (LPS), THP, or human recombinant epidermal growth factor (EGF) was evaluated by western blot. A p38 MAPK inhibitor, SB203580, effectively inhibited both spontaneous and LPS-and THP-induced PMN phagocytosis. Both THP and LPS enhanced the expression of the Rho family proteins Cdc42 and Rac that may lead to F-actin re-arrangement. Further studies suggested that THP and EGF enhance PMN and differentiated HL-60 cell phagocytosis in a similar pattern. Furthermore, the EGF receptor inhibitor GW2974 significantly suppressed THP-and EGF-enhanced PMN phagocytosis and p38 and ERK1/2 phosphorylation in differentiated HL-60 cells. We conclude that EGF receptor-dependent signaling may be involved in THP-enhanced PMN phagocytosis by activating Rho family and MAP kinase.

Infectious complications in cancer patients treated with anti-EGFR monoclonal antibodies cetuximab and panitumumab: A systematic review and meta-analysis

“…Lewkowicz et al showed that EGF significantly enhances TNF-a-induced respiratory burst and phagocytic activity through EGFR tyrosine kinase pathway [51]. Recently, Li et al reported EGFR is involved in the Tamm-Horsfall glycoprotein-enhanced neutrophil phagocytosis which was significantly suppressed by the EGFR inhibitor GW2974 [52]. Further studies are needed, as multiple distinct mechanisms could underlie the pathogenesis of the increased risk of infection with anti-EGFR mAbs.…”

Intracellular Trafficking Modulation by Ginsenoside Rg3 Inhibits Brucella abortus Uptake and Intracellular Survival within RAW 264.7 Cells

“…In agreement with the previous study, this study showed that Rg3 attenuated the activation of MAPKs (ERK 1/2 and p38) in B. abortus-infected cells. Moreover, it has been proven that the MAPK signaling pathway is involved in promoting actin polymerization [21] and polymorphonuclear neutrophil phagocytosis [22]. Studies of Kusumawati et al [23] and Guzman-Verri et al [24] elucidated that F-actin polymerization is also involved in the phagocytosis of Brucella in macrophages and epithelial cells.…”

Tamm–Horsfall Protein is a Potent Immunomodulatory Molecule and a Disease Biomarker in the Urinary System

“…Siao et al [ 79 ] and Li et al [ 36 ] have investigated the molecular basis of THP-enhanced PMN phagocytosis. They have found that THP, through its EGF-like domains, binds to EGF receptors or surface-expressed lactoferrin and cathepsin G on PMN to activate Rho family molecules (Cdc, Rac, and RhoA) and mitogen-activated protein kinase signaling pathways.…”

“…The molecule is directly excreted into the urine stream after production. ( B ) The domain structure of the THP molecule shows 3 epidermal growth factor (EGF)-like domains (marked by EGF-1, EGF-2, EGF-3), 7 N -glycosylation sites (marked by Y), and a proteinase cleavage site (marked by X) (adapted from Li et al [ 36 ]). ( C ) Fine tetra-antennary carbohydrate composition of THP and its binding site with the blood substance Sd a (from Serafini-Cessi et al [ 37 ]).…”