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Akt/protein kinase B activation by adenovirus vectors contributes to NFkappaB-dependent CXCL10 expression.
J Virol. 2005 Dec; 79(23):14507-15.JV

Abstract

In gene therapy, the innate immune system is a significant barrier to the effective application of adenovirus (Ad) vectors. In kidney epithelium-derived (REC) cells, serotype 5 Ad vectors induce the expression of the chemokine CXCL10 (IP-10), a response that is dependent on NFkappaB. Compared to the parental vector AdLuc, transduction with the RGD-deleted vector AdL.PB resulted in reduced CXCL10 activation despite increasing titers, implying that RGD-alpha(V) integrin interactions contribute to adenovirus induction of inflammatory genes. Akt, a downstream effector of integrin signaling, was activated within 10 min of transduction with Ad vectors in a dose-dependent manner. Akt activation was not present following transduction with AdL.PB, confirming the importance of capsid-alpha(V) integrin interactions in Ad vector Akt activation. Inhibition of the phosphoinositide-3-OH kinase/Akt pathway by Wortmannin or Ly294002 compounds decreased Ad vector induction of CXCL10 mRNA. Similarly, adenovirus-mediated overexpression of the dominant negative AktAAA decreased CXCL10 mRNA expression compared to the reporter vector AdLacZ alone. The effect of Akt on CXCL10 mRNA expression occurred via NFkappaB-dependent transcriptional activation, since AktAAA overexpression and Ly294002 both inhibited CXCL10 and NFkappaB promoter activation in luciferase reporter experiments. These results show that Akt plays a role in the Ad vector activation of NFkappaB and CXCL10 expression. Understanding the mechanism underlying the regulation of host immunomodulatory genes by adenovirus vectors will lead to strategies that will improve the efficacy and safety of these agents for clinical use.

Authors+Show Affiliations

Department of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16282450

Citation

Liu, Qiang, et al. "Akt/protein Kinase B Activation By Adenovirus Vectors Contributes to NFkappaB-dependent CXCL10 Expression." Journal of Virology, vol. 79, no. 23, 2005, pp. 14507-15.
Liu Q, White LR, Clark SA, et al. Akt/protein kinase B activation by adenovirus vectors contributes to NFkappaB-dependent CXCL10 expression. J Virol. 2005;79(23):14507-15.
Liu, Q., White, L. R., Clark, S. A., Heffner, D. J., Winston, B. W., Tibbles, L. A., & Muruve, D. A. (2005). Akt/protein kinase B activation by adenovirus vectors contributes to NFkappaB-dependent CXCL10 expression. Journal of Virology, 79(23), 14507-15.
Liu Q, et al. Akt/protein Kinase B Activation By Adenovirus Vectors Contributes to NFkappaB-dependent CXCL10 Expression. J Virol. 2005;79(23):14507-15. PubMed PMID: 16282450.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Akt/protein kinase B activation by adenovirus vectors contributes to NFkappaB-dependent CXCL10 expression. AU - Liu,Qiang, AU - White,Lindsay R, AU - Clark,Sharon A, AU - Heffner,Daniel J, AU - Winston,Brent W, AU - Tibbles,Lee Anne, AU - Muruve,Daniel A, PY - 2005/11/12/pubmed PY - 2006/1/24/medline PY - 2005/11/12/entrez SP - 14507 EP - 15 JF - Journal of virology JO - J Virol VL - 79 IS - 23 N2 - In gene therapy, the innate immune system is a significant barrier to the effective application of adenovirus (Ad) vectors. In kidney epithelium-derived (REC) cells, serotype 5 Ad vectors induce the expression of the chemokine CXCL10 (IP-10), a response that is dependent on NFkappaB. Compared to the parental vector AdLuc, transduction with the RGD-deleted vector AdL.PB resulted in reduced CXCL10 activation despite increasing titers, implying that RGD-alpha(V) integrin interactions contribute to adenovirus induction of inflammatory genes. Akt, a downstream effector of integrin signaling, was activated within 10 min of transduction with Ad vectors in a dose-dependent manner. Akt activation was not present following transduction with AdL.PB, confirming the importance of capsid-alpha(V) integrin interactions in Ad vector Akt activation. Inhibition of the phosphoinositide-3-OH kinase/Akt pathway by Wortmannin or Ly294002 compounds decreased Ad vector induction of CXCL10 mRNA. Similarly, adenovirus-mediated overexpression of the dominant negative AktAAA decreased CXCL10 mRNA expression compared to the reporter vector AdLacZ alone. The effect of Akt on CXCL10 mRNA expression occurred via NFkappaB-dependent transcriptional activation, since AktAAA overexpression and Ly294002 both inhibited CXCL10 and NFkappaB promoter activation in luciferase reporter experiments. These results show that Akt plays a role in the Ad vector activation of NFkappaB and CXCL10 expression. Understanding the mechanism underlying the regulation of host immunomodulatory genes by adenovirus vectors will lead to strategies that will improve the efficacy and safety of these agents for clinical use. SN - 0022-538X UR - https://www.unboundmedicine.com/medline/citation/16282450/Akt/protein_kinase_B_activation_by_adenovirus_vectors_contributes_to_NFkappaB_dependent_CXCL10_expression_ L2 - https://journals.asm.org/doi/10.1128/JVI.79.23.14507-14515.2005?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -