MAP kinases and NF-kappaB collaborate to induce ICAM-1 gene expression in the early phase of adenovirus infection.
Replication-defective adenoviruses (Ad) utilized as vectors for gene transfer are known to induce an inflammatory and immune response upon exposure to respiratory cells in vitro and in vivo. Among the different mediators of inflammation, we recently demonstrated that a replication-defective Ad serotype 5, deleted in the early genes E1 and E3 (Ad.CFTR), induces the proinflammatory intercellular adhesion molecule 1 (ICAM-1) in A549 respiratory cells in vitro and in lung portions of nonhuman primates in vivo, Gene Ther. 5, 131-136). More recently, we described the involvement of the nuclear factor kappaB (NF-kappaB) in the induction of ICAM-1 upon 24 h of exposure of the same Ad5-derived vector, Gene Ther. 8, 1436-1442). Here we investigated whether the early phase of virus-cell interaction is sufficient to stimulate ICAM-1 upregulation. A549 cells were exposed to wild-type Ad5 (Ad5), to Ad.CFTR, and to Ad5 inactivated by incubation at 56 degrees C (Ad5/56 degrees C). Ad5, Ad.CFTR, and Ad5/56 degrees C activated NF-kappaB and increased ICAM-1 mRNA levels within 4 h after exposure. The role of the mitogen-activated protein kinases (MAPKs) on the ICAM-1 mRNA induction was studied. ICAM-1 mRNA upregulation was inhibited upon incubation with several chemicals, namely, the ERK1/2 inhibitors PD98059 and AG1288 (by 98 and 67%, respectively), of the p38/MAPK pathway SB203580 (by 50%), of the JNK pathway dimethylaminopurine (by 83%), and of the NF-kappaB parthenolide (by 96%). Ad5 and Ad5/56 degrees C stimulated ERK1/2, p38/MAPK, and JNK1 starting 10 min and peaking 20-30 min after exposure. The present results indicate a link between the activation of the three major MAPK pathways, NF-kappaB, and the upregulation of ICAM-1 gene expression evoked by Ad5 in the very initial phase of infection.
Tamanini
Anna
A
Laboratory of Molecular Pathology, Cystic Fibrosis Center, I-37126, Verona, Italy.
Rolfini
Rossella
R
Nicolis
Elena
E
Melotti
Paola
P
Cabrini
Giulio
G
D021581:Active Transport, Cell Nucleus; D000256:Adenoviridae / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases