title: Up-regulation of ERK and p38 MAPK signaling pathways by hepatitis C virus E2 envelope protein in human T lymphoma cell line.
abstract: Hepatitis C virus (HCV) infection correlates with human immune disorders characterized by abnormal activation and proliferation of lymphocytes. Interaction of HCV major envelope protein E2 with susceptible cells occurs at an early stage of the viral infection. HCV tropism for susceptible cells may elicit cellular signaling events implicated in the viral pathogenicity, and E2 protein is known to be responsible for the tropism. We documented previously that HCV E2 protein was capable of activating extracellular signal-regulated kinase (ERK) in human hepatoma Huh-7 cells. Here, ERK and p38 mitogen-activated protein kinase (MAPK) signaling pathways were investigated in human T lymphoma cell line Molt-4 in response to HCV E2 protein. Binding of HCV E2 protein to Molt-4 cells was detectable, and such interaction was a determinant for recognition and delivery of the E2 signal to intracellular pathways. Activation of ERK and p38 MAPK was specifically induced following the HCV E2-cell interaction. CD81 and low-density lipoprotein receptor (LDLR), proposed cellular receptors for HCV, were expressed naturally on Molt-4 cells. CD81 and LDLR were shown to mediate HCV E2-induced activation of ERK and p38 MAPK. In CD81-deficient U937 cells, levels of ERK and p38 MAPK activation and cell proliferation induced by HCV E2 protein were lower than those in Molt-4 cells. Furthermore, cell proliferation and secretion of interferon-gamma and interleukin-10 by Molt-4 cells were promoted by HCV E2 protein. Therefore, ERK and p38 MAPK signaling pathways were up-regulated by HCV E2 protein without synergetic stimulation, which was accompanied by alterations of cell behavior.
authors.affiliation: State key Laboratory of Medical Immunology and Department of Microbiology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Lan-Juan
authors.initials: LJ
authors.lastname: Zhao
authors.forename: Xiao-Lian
authors.initials: XL
authors.lastname: Zhang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.forename: Ming-Mei
authors.initials: MM
authors.lastname: Cao
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Zhu
authors.forename: Hou-Qi
authors.initials: HQ
authors.lastname: Liu
authors.forename: Zhong-Tian
authors.initials: ZT
authors.lastname: Qi
mesh_terms: D015703:Antigens, CD / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D016399:Lymphoma, T-Cell / Q000378:metabolism*; D011973:Receptors, LDL / Q000502:physiology; D015398:Signal Transduction; D060225:Tetraspanin 28; D015854:Up-Regulation; D014759:Viral Envelope Proteins / Q000378:metabolism / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; D016207:Cytokines; D011973:Receptors, LDL; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases