Heme oxygenase 1 mediates the immunomodulatory and antiapoptotic effects of interleukin 13 gene therapy in vivo and in vitro

Bibo Ke, Xiu Da Shen, Yuan Zhai, Feng Gao, Ronald W. Busuttil, Hans Dieter Volk, Jerzy W. Kupiec-Weglinski

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


This study analyzes mechanisms by which interleukin 13 (IL-13) affects "infectious tolerance" in rat recipients of cardiac allografts, with emphasis on interactions between intragraft Ad-IL-13 gene transfer and systemic infusion of regulatory cells. Although exogenous viral IL-13 was modestly effective on its own, adjunctive Ad-IL-13 gene therapy and adoptive transfer of suboptimal dose of regulatory T cells exerted synergistic effects, as evidenced by long-term cardiac allograft survival in test recipients. Local IL-13 induction (determined by enzyme-linked immunosorbent assay and immunohistology) diminished intragraft apoptosis, and upregulated antiapoptotic A20 and antioxidant heme oxygenase 1 (HO-1). Ad-IL-13 plus regulatory cells synergistically diminished the frequency of cells positive by TUNEL (TdT [terminal deoxynucleotidyltransferase]-mediated dUTP nick-end labeling) assay, and enhanced cytoprotective gene expression. These findings correlated with in vitro studies in which Ad-IL-13 decreased tumor necrosis factor α (TNF-α)-mediated cytotoxicity, conferred resistance to apoptosis, and increased HO-1/A20 expression in human umbilical vein endothelial cell (HUVEC) cultures. However, inhibition of HO-1 after treatment with tin protoporphyrin reversed the immunomodulatory/antiapoptotic effects of Ad-IL-13 both in vivo (infectious transplantation tolerance), and in vitro (HUVECs). Thus, by decreasing apoptosis/TNF-α-mediated cytotoxicity, and by facilitating induction of antiapoptotic/antioxidant molecules in HUVECs, this study documents the cytoprotective function of Ad-IL-13 in vitro, and points toward in vivo synergy between Ad-IL-13 and regulatory cells in the infectious transplantation tolerance pathway. Results of HO-1 neutralization studies suggest that HO-1 represents one of the putative IL-13 downstream effectors.

Original languageEnglish (US)
Pages (from-to)1845-1857
Number of pages13
JournalHuman Gene Therapy
Issue number15
StatePublished - 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics


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