Overexpression of heme oxygenase (HO)-1 renders Jurkat T cells resistant to fas-mediated apoptosis: involvement of iron released by HO-1.
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 IkappaB kinase (IKK) activation via iron-induced reactive oxygen species formation, NF-kappaB activation by activated IKK, and c-FLIP expression by activated NF-kappaB. 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.
Choi
Byung-Min
BM
Genomic Research Center for Immune Disorders and Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, Chonbuk, Republic of Korea.
Pae
Hyun-Ock
HO
Jeong
Young-Ran
YR
Oh
Gi-Su
GS
Jun
Chang-Duk
CD
Kim
Bok-Ryang
BR
Kim
Young-Myeong
YM
Chung
Hun-Taeg
HT
D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D005434:Flow Cytometry; D019254:Genes, bcl-2 / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D007120:Immunochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D019169:Jurkat Cells; D008565:Membrane Proteins; D016328:NF-kappa B / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D020169:Caspases; D018076:DNA, Complementary; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D047908:Intracellular Signaling Peptides and Proteins; D007501:Iron; D008565:Membrane Proteins; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; D019014:fas Receptor; D000097782:NF-kappaB-Inducing Kinase; C506386:CFLAR protein, human; C007095:cobaltiprotoporphyrin; C496541:HMOX1 protein, human