title: NF-kappa B activation plays an important role in the IL-4-induced protection from apoptosis.
abstract: IL-4 alone protects cells from apoptosis by insulin receptor substrate (IRS)-dependent and -independent mechanisms. However, in vivo cells are typically exposed to a number of signals at the same time. To determine the contribution of co-stimulatory signals to the regulation of apoptosis by IL-4, we first analyzed whether tumor necrosis factor (TNF)-alpha, which has been shown to inhibit the activation of IRS-1 by insulin, could modify IL-4 signaling and protection from apoptosis. We found that TNF-alpha cooperates with IL-4 in protecting 32D cells from factor withdrawal-induced apoptosis. This effect was independent of the expression of IRS-1, indicating that this cooperation is via an alternative anti-apoptotic pathway. Moreover, TNF-alpha had no effect on the activation of IRS-1 induced by IL-4. IL-4 enhanced TNF-alpha-induced activation of the transcription factor NF-kappaB. Interestingly, pharmacologic inhibition of NF-kappaB activation or protein synthesis resulted in the induction of cell death that could not be inhibited by IL-4, suggesting that IL-4 cooperates with NF-kappaB to signal protection from apoptosis. Supporting this hypothesis, IL-4 also increased NF-kappaB activation induced by anti-CD3 antibodies in primary T cells and protected them from apoptosis induced by receptor engagement. However, IL-4 was not able to inhibit apoptosis induced by anti-CD3 in T lymphocytes isolated from transgenic mice expressing a dominant-negative form of IkappaBalpha that prevents NF-kappaB activation. Thus, in addition to the previously identified IRS-1 pathway, IL-4-induced protection from apoptosis may also be mediated through cooperation with the NF-kappaB family of transcription factors.
authors.affiliation: Department of Immunology, Holland Laboratory, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zamorano
authors.forename: A L
authors.initials: AL
authors.lastname: Mora
authors.forename: M
authors.initials: M
authors.lastname: Boothby
authors.forename: A D
authors.initials: AD
authors.lastname: Keegan
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D055504:Insulin Receptor Substrate Proteins; D015847:Interleukin-4 / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D016328:NF-kappa B; D010750:Phosphoproteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D011972:Receptor, Insulin