Overexpression of heme oxygenase (HO)-1 renders jurkat T cells resistant to Fas-mediated apoptosis: involvement of iron released by HO-1

• Published in: Free radical biology & medicine 2004-04, Vol.36 (7), p.858-871
• Main Authors: Choi, Byung-Min, Pae, Hyun-Ock, Jeong, Young-Ran, Oh, Gi-Su, Jun, Chang-Duk, Kim, Bok-Ryang, Kim, Young-Myeong, Chung, Hun-Taeg
• Format: Article
• Language: English
• Subjects: Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspases - metabolism; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - enzymology; CD4-Positive T-Lymphocytes - metabolism; DNA, Complementary - genetics; fas Receptor - metabolism; Flow Cytometry; Free radicals; Genes, bcl-2 - physiology; Heme Oxygenase (Decyclizing) - genetics; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1; Humans; Immunochemistry; Intracellular Signaling Peptides and Proteins - metabolism; Iron; Iron - metabolism; Jurkat Cells; Membrane Proteins; NF-kappa B - metabolism; NF-kappaB-Inducing Kinase; NF-κB; Oligonucleotides, Antisense - pharmacology; Protein Serine-Threonine Kinases - metabolism; Proteins - metabolism; Protoporphyrins - pharmacology; Reactive Oxygen Species - metabolism; T cell; Transfection
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2004.01.004

We recently demonstrated that heme oxygenase (HO)-1 is constitutively expressed in human CD4 +CD25 + regulatory T cells and induced by anti-CD28 or anti-CD28/anti-CD3 stimulation, even in CD4 +CD25 − responder T cells. To study the effects of HO-1 expression on lymphocyte survival, we transfected the HO-1 gene or induced the gene to express HO-1 protein with cobalt protoporphyrin (CoPP) in Jurkat T cells. Consistently, anti-Fas antibody triggered apoptotic cell death in wild-type Jurkat T cells. Surprisingly, however, HO-1-overexpressing Jurkat T cells showed strong resistance to Fas-mediated apoptosis. In contrast, abrogation of HO-1 expression by antisense oligomer against HO-1 gene from CoPP-treated cells or depletion of iron by desferrioxamine from HO-1-transfected cells abolished the resistance. In addition, exogenously added iron rendered wild-type Jurkat T cells resistant. The resistance involved IκB kinase (IKK) activation via iron-induced reactive oxygen species formation, NF-κB activation by activated IKK, and c-FLIP expression by activated NF-κB. Primary CD4 + T cells induced by CoPP to express HO-1 also showed more resistance to Fas-mediated apoptosis than untreated cells. Our findings suggest that HO-1 plays a critical and nonredundant role in Fas-mediated activation-induced cell death of T lymphocytes.