Cellular signals involved in cyclooxygenase-2 expression induced by human cytomegalovirus.
Cyclooxygenase (COX)-2 plays an important role in inflammatory reaction and human cytomegalovirus (HCMV) is known to induce COX-2 gene expression. However, little is known for the mechanism of COX-2 gene expression by HCMV. In this study, three recently isolated HCMV strains including TB40/E and clinical isolates from Korean patients as well as highly laboratory adapted strain AD169 were used to stimulate COX-2 induction. Western blot analyses revealed that recently isolated HCMV strains induced COX-2 expression in human foreskin fibroblast (HFF) cells to higher levels than lab-adapted strain AD169. HCMV gene expression was not required for COX-2 induction since UV-inactivated virus was able to stimulate COX-2 gene expression during immediate early infection. Moreover, when HCMV-infected HFF cells were transfected with small interfering RNA for major immediate early (MIE) genes, HCMV-induced COX-2 expression was not abrogated, suggesting that HCMV MIE genes are not needed for COX-2 expression. In order to understand the signal pathways involved in COX-2 gene expression induced by HCMV, selective inhibitors were used. When HCMV-infected HFF cells were treated with epidermal growth factor receptor (EGFR) kinase inhibitors and c-Raf/mitogen-activated protein kinases (MAPK, MEK) 1/2 inhibitors, HCMV-induced COX-2 expression was diminished. However, COX-2 expression by HCMV infection was not inhibited if HCMV-infected HFF cells were treated with inhibitors of phosphatidylinositol-3-kinase, c-Jun N-terminal kinase, nuclear factor kappa B, p-38 MAPK and Rho-associated protein kinase. We concluded that EGFRK, Raf, MEK1/2 and extracellular signal-regulated kinases (ERK 1/2) pathway may participate in the COX-2 mediated inflammatory response to HCMV infection.
Yi
Hyun Ah
HA
Department of Microbiology, Chungbuk National University, Cheongju, Chungbuk 361-763, South Korea.
Kim
Mi Suk
MS
Jang
So Young
SY
Lee
Young Min
YM
Ahn
Jin Hyun
JH
Lee
Chan Hee
CH
D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D003587:Cytomegalovirus / Q000302:isolation & purification / Q000472:pathogenicity*; D003586:Cytomegalovirus Infections / Q000821:virology; D066246:ErbB Receptors / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D007723:Korea; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism
D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D019908:Proto-Oncogene Proteins c-raf; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2