title: Depressed IL-12-mediated signal transduction in T cells from patients with Sézary syndrome is associated with the absence of IL-12 receptor beta 2 mRNA and highly reduced levels of STAT4.
abstract: Sézary syndrome (SS) is the leukemic phase of cutaneous T cell lymphoma characterized by the proliferation of clonally derived CD4+ T cells that release cytokines of the Th2 T cell phenotype (IL-4, IL-5, IL-10), whereas Th1 T cell cytokines (IL-2, IFN-gamma) are markedly depressed as is expression of IL-12, a pivotal cytokine for Th1 cell differentiation. Normal Th1 cells express both the beta 1 and beta 2 chains of the IL-12 receptor (IL-12R) and tyrosine phosphorylate STAT4 in response to IL-12. Th2 T cells express only the IL-12R beta 1 and thus do not tyrosine phosphorylate STAT4 in response to IL-12. To determine whether SS cells are Th2-like at the level of IL-12 signal transduction, we analyzed RNA from seven patients for the presence of message for the IL-12R beta 1 and beta 2 genes using RNase protection assays and assessed whether IL-12 induced tyrosine-phosphorylation of STAT4 by immunoblotting. In PBL from six of seven SS patients tested, beta 2 message was expressed at low to undetectable levels and its expression could not be stimulated by either IFN-alpha or IFN- gamma, which stimulated beta 2 expression in control PBL. The absence of beta 2 expression is further supportive evidence for the Th2 lineage of SS cells. However, unlike normal Th2 cells, SS cells also showed severely reduced levels of STAT4, suggesting that they have a depressed response to any inducer of the STAT4 signal transduction pathway, including IFN-alpha. This is the first observation linking STAT4 gene expression with a human disease and suggests that dysregulation of STAT4 expression may be significant to the development and/or progression of SS.
authors.affiliation: Wistar Institute of Anatomy and Biology, Philadelphia, PA 19104, USA. Lshowe@wistar.upenn.edu
authors.forename: L C
authors.initials: LC
authors.lastname: Showe
authors.forename: F E
authors.initials: FE
authors.lastname: Fox
authors.forename: D
authors.initials: D
authors.lastname: Williams
authors.forename: K
authors.initials: K
authors.lastname: Au
authors.forename: Z
authors.initials: Z
authors.lastname: Niu
authors.forename: A H
authors.initials: AH
authors.lastname: Rook
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000276:immunology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D012751:Sezary Syndrome / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D007106:Immune Sera; D016898:Interferon-alpha; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma