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HVEM Signaling in Monocytes Is Mediated by Intracellular Calcium Mobilization¹

Sook-Kyoung Heo^*, Min-A Yoon, Sang-Chul Lee, Seong-A Ju, Jang-Hyun Choi, Pann-Ghill Suh, Byoung S. Kwon^*, and Byung-Sam Kim^2,*,,

^* Department of Biomedicine, Department of Biological Sciences and Immunomodulation Research Center, University of Ulsan, Ulsan, South Korea; Department of Life Science, Pohang University of Science and Technology, Hyojadong, Pohang, Kyungbuk, South Korea

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 NFB activation as a result of IB 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 ([Ca²⁺]_i) in a HVEM-specific manner in parallel with TNF- production, and enhances the bactericidal activities of monocytes. Immunoprecipitation and Western blotting analyses revealed phosphorylation of phospholipase C1 (PLC1) but not PLC2. rhLIGHT-induced Ca²⁺response was completely abolished by silencing PLC1, or preincubating monocytes with PLC inhibitors, antagonists of the inositol-1,4,5-triphosphate receptor, or [Ca²⁺]_i chelators. Furthermore, these PLC/Ca²⁺ inhibitors also blocked rhLIGHT-mediated IB degradation, generation of reactive oxygen species, TNF- production and the bactericidal activities of monocytes. Our results indicate that Ca²⁺is a downstream mediator of the LIGHT/HVEM interaction in monocytes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Science Research Center Fund to the Immunomodulation Research Center at the University of Ulsan from KOSEF, the Ministry of Korean Science and Technology. S.-K.H., M.-A.Y., and S.-A.J. were supported by the Second Project of BK21, the Ministry of Korean Education and Human Resources Development.

² Address correspondence and reprint requests to Dr. Byung-Sam Kim, Department of Biological Sciences and Immunomodulation Research Center, University of Ulsan, Ulsan, South Korea. E-mail address: bskim{at}mail.ulsan.ac.kr

³ Abbreviations used in this paper: LIGHT, homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator (HVEM/TR2); PLC, phospholipase C; IP₃, inositol-1,4,5-trisphosphate; rhLIGHT, recombinant human LIGHT; gD, glycoprotein D; LTR, lymphotoxin receptor; XeC, xestospongin C; TRAF, TNFR-associated factor; siRNA, small interfering RNA; HI, heat inactivated; ROS, reactive oxygen species; DCF-DA, 2,7-dichlorofluorescein diacetate; SH, Src-homology domain.