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Journal of Virology, February 2002, p. 1559-1568, Vol. 76, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.4.1559-1568.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Activation of p38 and ERK Signaling during Adenovirus Vector Cell Entry Lead to Expression of the C-X-C Chemokine IP-10

Lee Anne Tibbles,1 Jason C. L. Spurrell,1 Gloria P. Bowen,1,2 Qiang Liu,1,2 Mindy Lam,1,2 Anne K. Zaiss,1,2 Stephen M. Robbins,3 Morley D. Hollenberg,4 Thomas J. Wickham,5 and Daniel A. Muruve1,2*

Department of Medicine,1 Libin Gene Therapy Unit,,2 Department of Oncology,,3 Department of Pharmacology and Therapeutics, University of Calgary Calgary, Alberta T2N 4N1, Canada,4 Research and Development, GenVec Inc., Gaithersburg, Maryland 208795

Received 22 June 2001/ Accepted 13 November 2001

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 AdCMVßgal. Inhibition of ERK and p38 with U0126 and SB203580, respectively, reduced the expression of IP-10 mRNA following transduction with AdCMVßgal. To determine the role of the coxsackievirus-adenovirus receptor (CAR) or {alpha}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.

* Corresponding author. Mailing address: Faculty of Medicine, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta T2N 4N1, Canada. Phone: (403) 220-3908. Fax: (403) 270-0979. E-mail: dmuruve{at}ucalgary.ca.

Journal of Virology, February 2002, p. 1559-1568, Vol. 76, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.4.1559-1568.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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