Melanoma differentiation-associated gene-7/IL-24 gene enhances NF-kappa B activation and suppresses apoptosis induced by TNF.
Melanoma differentiation-associated gene-7 (mda-7), also referred to as IL-24, is a novel growth regulatory cytokine that has been shown to regulate the immune system by inducing the expression of inflammatory cytokines, such as TNF, IL-1, and IL-6. Whether the induction of these cytokines by MDA-7 is mediated through activation of NF-kappaB or whether it regulates cytokine signaling is not known. In the present report we investigated the effect of MDA-7 on NF-kappaB activation and on TNF-induced NF-kappaB activation and apoptosis in human embryonic kidney 293 cells. Stable or transient transfection with mda-7 into 293 cells failed to activate NF-kappaB. However, TNF-induced NF-kappaB activation was significantly enhanced in mda-7-transfected cells, as indicated by DNA binding, p65 translocation, and NF-kappaB-dependent reporter gene expression. Mda-7 transfection also potentiated NF-kappaB reporter activation induced by TNF receptor-associated death domain and TNF receptor-associated factor-2. Cytoplasmic MDA-7 with deleted signal sequence was as effective as full-length MDA-7 in potentiating TNF-induced NF-kappaB reporter activity. Secretion of MDA-7 was not required for the potentiation of TNF-induced NF-kappaB activation. TNF-induced expression of the NF-kappaB-regulated gene products cyclin D1 and cyclooxygenase-2, were significantly up-regulated by stable expression of MDA-7. Furthermore, MDA-7 expression abolished TNF-induced apoptosis, and suppression of NF-kappaB by IkappaBalpha kinase inhibitors enhanced apoptosis. Overall, our results indicate that stable or transient MDA-7 expression alone does not substantially activate NF-kappaB, but potentiates TNF-induced NF-kappaB activation and NF-kappaB-regulated gene expression. Potentiation of NF-kappaB survival signaling by MDA-7 inhibits TNF-mediated apoptosis.
Aggarwal
Sita
S
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Takada
Yasunari
Y
Mhashilkar
Abner M
AM
Sieger
Kerry
K
Chada
Sunil
S
Aggarwal
Bharat B
BB
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000276:immunology*; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D019938:Cyclin D1 / Q000096:biosynthesis; D051546:Cyclooxygenase 2; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000276:immunology; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor; D006801:Humans; D051550:I-kappa B Kinase; D007378:Interleukins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007527:Isoenzymes / Q000096:biosynthesis; D008545:Melanoma / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D011506:Proteins / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000099180:Interleukin-24
D000276:Adjuvants, Immunologic; D000469:Alkaline Phosphatase; D002352:Carrier Proteins; D019938:Cyclin D1; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D007378:Interleukins; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D011451:Prostaglandin-Endoperoxide Synthases; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D000099180:Interleukin-24; C491731:IKBKG protein, human; C496540:PTGS2 protein, human