title: IL-12 inhibits glucocorticoid-induced T cell apoptosis by inducing GMEB1 and activating PI3K/Akt pathway.
abstract: Interleukin (IL)-12 is an important pro-inflammatory cytokine that has been shown to play a role in T cell survival, at least in part by activating the PI3K/Akt pathway. Glucocorticoid modulatory element binding protein (GMEB)1 and 2 are closely related proteins that modify the glucocorticoid receptor binding locus and thus modulate glucocorticoid-mediated gene induction effects, including apoptosis. GMEB1 associates with caspases and prevents apoptosis of cells in the nervous system. We have observed, in preliminary studies, that IL-12 up-regulates GMEB mRNA in human T cells, and postulated that this may contribute to the anti-apoptotic effect of IL-12 on T cells, in particular with regard to glucocorticoid induced apoptosis. Here, we confirm that IL-12 rescue of dexamethasone induced T cell apoptosis involves the PI3K/Akt pathway and that IL-12 induces GMEB1 and GMEB2. A siRNA knockdown of GMEB1 reverses the protective effect of IL-12 on dexamethasone induced T cell apoptosis. Thus, IL-12 protects T cells from glucocorticoid induced apoptosis via PI3K/Akt pathway and via induction of GMEB1, which is likely to reduce transactivation of the glucocorticoid receptor and induction of apoptotic genes. As glucocorticoid induced apoptosis occurs both in physiological and pathological/therapeutic situations, and IL-12 is actively involved in a variety of inflammatory and immune responses, the ability of IL-12 to inhibit steroid responses and increase T cell survival through GMEB1 has wide ranging implications. Manipulating GMEB may be used therapeutically to enhance the resistance or the sensitivity to steroids.
authors.affiliation: Division of Clinical Neurology, University of Nottingham, United Kingdom.
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Kawabe
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindsay
authors.forename: Manjit
authors.initials: M
authors.lastname: Braitch
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Fahey
authors.forename: Louise
authors.initials: L
authors.lastname: Showe
authors.forename: Cris S
authors.initials: CS
authors.lastname: Constantinescu
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000276:immunology; D055785:Gene Knockdown Techniques; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D003907:Dexamethasone; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D018664:Interleukin-12; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; C490664:GMEB1 protein, human; C490663:GMEB2 protein, human