Tumor necrosis factor-alpha potentiates RhoA-mediated monocyte transmigratory activity in vivo at a picomolar level.
OBJECTIVE
The serum level of tumor necrosis factor-alpha (TNF-alpha) is in the picomolar range under inflammatory conditions. We investigated whether these picomolar levels of TNF-alpha directly modulate the functional activities of circulating monocytes.


RESULTS
In THP-1 monocytes treated with TNF-alpha (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-kappaB 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, PKCzeta. The TNF-alpha-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-alpha augmented MCP-1-mediated chemotaxis and firm adhesion on VCAM-1 and ICAM-1 in vitro and ex vivo. The elevation of serum TNF-alpha (>5 pmol/L within 16 hours), which was introduced by intraperitoneal injection of mouse-specific TNF-alpha to C57/BL6 mice, enhanced the number of CD80+ monocytes transmigrating to the JE/MCP-1-injected intraperitoneal space.


CONCLUSIONS
Picomolar concentrations of TNF-alpha in the bloodstream may prime the RhoA-dependent activities of circulating monocytes to enhance recruitment to active inflammatory foci.
Lim
Sunny
S
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Ryu
Jewon
J
Shin
Jin-Ae
JA
Shin
Min-Jung
MJ
Ahn
Yeong Ki
YK
Kim
Jae Joong
JJ
Han
Ki Hoon
KH
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D018932:Chemokine CCL2 / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010529:Peritoneal Cavity / Q000166:cytology; D010766:Phosphorylation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000502:physiology*; D000099149:Ezrin
D018932:Chemokine CCL2; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000099149:Ezrin; C111835:CCL2 protein, human; C066737:RHOA protein, human; C071058:moesin; C071776:radixin; C526380:RhoA protein, mouse