HVEM signaling in monocytes is mediated by intracellular calcium mobilization.
Herpes virus entry mediator (HVEM) is a member of the TNF receptor (TNFR) superfamily and is expressed on many immune cells, including T and B cells, NK cells, monocytes, and neutrophils. Interaction of HVEM with its ligand, LIGHT, costimulates T cells and increases the bactericidal activity of monocytes and neutrophils. The interaction recruits cytoplasmic TNFR-associated factor adaptor proteins to the intracellular domain of HVEM. This leads to NFkappaB activation as a result of IkappaBalpha degradation and/or JNK/AP-1 activation, and ultimately results in the expression of genes required for cell survival, cytokine production, or cell proliferation. In this study, we show that treatment of human monocytes with recombinant human LIGHT (rhLIGHT) induces rapid elevation of intracellular calcium concentration ([Ca(2+)](i)) in a HVEM-specific manner in parallel with TNF-alpha production, and enhances the bactericidal activities of monocytes. Immunoprecipitation and Western blotting analyses revealed phosphorylation of phospholipase Cgamma1 (PLCgamma1) but not PLCgamma2. rhLIGHT-induced Ca(2+)response was completely abolished by silencing PLCgamma1, or preincubating monocytes with PLC inhibitors, antagonists of the inositol-1,4,5-triphosphate receptor, or [Ca(2+)](i) chelators. Furthermore, these PLC/Ca(2+) inhibitors also blocked rhLIGHT-mediated IkappaBalpha degradation, generation of reactive oxygen species, TNF-alpha production and the bactericidal activities of monocytes. Our results indicate that Ca(2+)is a downstream mediator of the LIGHT/HVEM interaction in monocytes.
Heo
Sook-Kyoung
SK
Department of Biomedicine, Immunomodulation Research Center, University of Ulsan, Ulsan, South Korea.
Yoon
Min-A
MA
Lee
Sang-Chul
SC
Ju
Seong-A
SA
Choi
Jang-Hyun
JH
Suh
Pann-Ghill
PG
Kwon
Byoung S
BS
Kim
Byung-Sam
BS
D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000378:metabolism*; D015398:Signal Transduction; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D017382:Reactive Oxygen Species; D053240:Receptors, Tumor Necrosis Factor, Member 14; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D019000:Phosphotyrosine; D051966:Phospholipase C gamma; D002118:Calcium