title: Inhibition of cellular FLICE-like inhibitory protein abolishes insensitivity to interferon-α and death receptor stimulation in resistant variants of the human U937 cell line.
abstract: Type I interferons constitute a family of pleiotropic cytokines that have a key role in both adaptive and innate immunity. The interferon signalling pathways mediate transcriptional regulation of hundreds of genes, which result in mRNA degradation, decreased protein synthesis, cell cycle inhibition and induction of apoptosis. To elucidate regulatory networks important for interferon induced cell death, we generated interferon resistant U937 cells by selection in progressively increasing concentrations of interferon-α (IFN-α). The results show that IFN-α activates the death receptor signalling pathway and that IFN resistance was associated with cross-resistance to several death receptor ligands in a manner similar to previously described Fas resistant U937 cell lines. Increased expression of the long splice variant of the cellular FLICE-like inhibitor protein (cFLIP-L) was associated with the resistance to death receptor and IFN-α stimulation. Accordingly, inhibition of cFLIP-L expression with cycloheximide or through cFLIP short harpin RNA interference restored sensitivity to Fas and/or IFN-α. Thus, we now show that selection for interferon resistance can generate cells with increased expression of cFLIP, which protects the cells from both IFN-α and death receptor mediated apoptosis.
authors.affiliation: Department of Medical Chemistry and Biophysics, Umeå University, 90187 Umeå, Sweden. jeanette.blomberg@medchem.umu.se
authors.forename: Jeanette
authors.initials: J
authors.lastname: Blomberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Höglund
authors.forename: David
authors.initials: D
authors.lastname: Eriksson
authors.forename: Kristina
authors.initials: K
authors.lastname: Ruuth
authors.forename: Maria
authors.initials: M
authors.lastname: Jacobsson
authors.forename: Erik
authors.initials: E
authors.lastname: Lundgren
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Nilsson
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004351:Drug Resistance; D004789:Enzyme Activation; D057075:Enzyme Assays; D005786:Gene Expression Regulation; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000502:physiology; D007399:Interphase; D034622:RNA Interference; D053218:Receptors, Death Domain / Q000378:metabolism*; D020298:U937 Cells; D015854:Up-Regulation
chemical_list: D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C421307:FAIM protein, human; D016898:Interferon-alpha; D053218:Receptors, Death Domain; D003513:Cycloheximide; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9