Activation of p38 and ERK Signaling during Adenovirus Vector Cell Entry Lead to Expression of the C-X-C Chemokine IP-10
Open Access
- 15 February 2002
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 76 (4) , 1559-1568
- https://doi.org/10.1128/jvi.76.4.1559-1568.2002
Abstract
The use of adenovirus vectors for human gene therapy is limited by potent inflammatory responses that result in significant morbidity. In kidney-derived epithelial cells (REC), activation of extracellular signal-regulated kinase 1/2 (ERK) and p38 kinase (p38) pathways occurred within 20 min of transduction with the serotype 5 adenovirus vector AdCMVβgal. Inhibition of ERK and p38 with U0126 and SB203580, respectively, reduced the expression of IP-10 mRNA following transduction with AdCMVβgal. To determine the role of the coxsackievirus-adenovirus receptor (CAR) or α v integrins in the activation of ERK and p38 and the expression of IP-10, REC cells were transduced with the fiber-modified and RGD-deleted adenovirus vectors AdL.F(RAEK-HA) and AdL.PB(HA), respectively. Compared with the wild-type capsid vector Ad5Luc, transduction with AdL.F(RAEK-HA) and AdL.PB(HA) resulted in reduced ERK-p38 activation and less IP-10 mRNA expression. The decreased IP-10 expression induced by the tropism-modified vectors was due to diminished transduction, since increasing multiplicity of infection resulted in increased IP-10 expression. Inhibition of adenovirus penetration with bafilomycin A1 or ammonium chloride attenuated the activation of ERK-p38 and IP-10 mRNA expression following infection, suggesting that endosomal escape was required to trigger these pathways. In vivo, direct inhibition of ERK and p38 signaling pathways inhibited adenovirus vector-induced IP-10 expression in mouse liver 1 h following transduction. These results demonstrate the importance of signaling via ERK and p38 in the early host response to adenovirus vectors and will permit the development of novel strategies to improve the safety and efficacy of these agents in human gene therapy.Keywords
This publication has 67 references indexed in Scilit:
- Integrin αvβ1 Is an Adenovirus CoreceptorJournal of Virology, 2001
- Gene Therapy's Web of Corporate ConnectionsScience, 2000
- Regulation of Adenovirus Membrane Penetration by the Cytoplasmic Tail of Integrin β5Journal of Virology, 2000
- SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin‐1Published by Wiley ,2000
- Integrin SignalingScience, 1999
- Adenoviral Gene Therapy Leads to Rapid Induction of Multiple Chemokines and Acute Neutrophil-Dependent Hepatic Injury in VivoHuman Gene Therapy, 1999
- Nonspecific Inflammation Inhibits Adenovirus-Mediated Pulmonary Gene Transfer and Expression Independent of Specific Acquired Immune ResponsesHuman Gene Therapy, 1998
- The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions.Journal of Clinical Investigation, 1998
- Pulmonary Inflammation Induced by Incomplete or Inactivated Adenoviral ParticlesHuman Gene Therapy, 1995
- Integrins αvβ3 and αvβ5 promote adenovirus internalization but not virus attachmentCell, 1993