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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:2138.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Tumor Necrosis Factor- Potentiates RhoA-Mediated Monocyte Transmigratory Activity In Vivo at a Picomolar Level

Sunny Lim; Jewon Ryu; Jin-Ae Shin; Min-Jung Shin; Yeong Ki Ahn; Jae Joong Kim; Ki Hoon Han

From the Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Correspondence to Ki Hoon Han, Asan Medical Center, University of Ulsan, College of Medicine, 388-1 Pungnap-2 dong Songpa-gu 138-736, Seoul, South Korea. E-mail steadyhan{at}amc.seoul.kr

Objective— The serum level of tumor necrosis factor- (TNF-) is in the picomolar range under inflammatory conditions. We investigated whether these picomolar levels of TNF- directly modulate the functional activities of circulating monocytes.

Methods and Results— In THP-1 monocytes treated with TNF- (1 to 100 pmol/L/30 minutes), cytosolic RhoA small GTPase rapidly translocated to the plasma membrane via functionally active ezrin/radixin/moesin (ERM) complex, a cytoskeletal linker, and subsequent actin polymerization through NF-B activation. The threonine phosphorylation of ERM was accomplished by the activation of TNF receptor type I (TNFRI) and signaling pathways involving PI3K and an atypical PKC; ie, PKC. The TNF--treated monocytes (10 pmol/L) displayed more potent and prolonged generation of GTP-bound RhoA in response to secondary stimulation with RhoA-activating monocyte chemoattractant protein-1 (MCP-1). Clearly, human circulating monocytes preconditioned by 10 pmol/L TNF- augmented MCP-1–mediated chemotaxis and firm adhesion on VCAM-1 and ICAM-1 in vitro and ex vivo. The elevation of serum TNF- (>5 pmol/L within 16 hours), which was introduced by intraperitoneal injection of mouse-specific TNF- to C57/BL6 mice, enhanced the number of CD80+ monocytes transmigrating to the JE/MCP-1–injected intraperitoneal space.

Conclusions— Picomolar concentrations of TNF- in the bloodstream may prime the RhoA-dependent activities of circulating monocytes to enhance recruitment to active inflammatory foci.

In response to picomolar levels of TNF- detected in serum under inflammatory conditions, human monocytes display enhanced translocation of RhoA to the plasma membrane via ezrin/radixin/moesin complex that is phosphorylated by TNFRI-derived PKC. Monocytes pretreated with picomolar TNF- eventually display more potent RhoA-mediated transmigration in response to MCP-1 in vivo.

Key Words: tumor necrosis factor- (TNF-) • RhoA • monocyte • Ezrin/Radixin/moesin (ERM) • transmigration