title: Interleukin-4 supports interleukin-12-induced proliferation and interferon-gamma secretion in human activated lymphoblasts and T helper type 1 cells.
abstract: Interleukin-12 (IL-12) and IL-4 are known to differentially promote T helper (Th) cell differentiation. While IL-12 induces interferon-gamma (IFN-gamma) production and maturation of Th1 cells, IL-4 is thought to antagonize IL-12 and to favour Th2 development. Here we studied the combined action of various concentrations of common gamma-chain (gamma(c)-chain) cytokines, including IL-4 and the Th1 cytokine IL-12, in human activated lymphoblasts and Th1 cells. IL-4 and IL-7 potentiated IL-12-induced proliferation at every concentration tested (1-10 ng/ml) without increasing rescue from apoptosis, indicating that proliferation was directly affected by these cytokine combinations. With regards to cytokine secretion, IL-2 together with IL-12 initiated tumour necrosis factor-alpha synthesis, enhanced IFN-gamma production, and shedding of soluble IL-2 receptor alpha as expected. Importantly, combining IL-4 with IL-12 also enhanced IFN-gamma secretion in lymphoblasts and a Th1 cell line. Investigating signal transduction in lymphoblasts induced by these cytokines, we found that not only IL-2 but also IL-4 enhances signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation by IL-12. Tyrosine phosphorylations of janus kinase 2 (JAK-2), tyrosine kinase 2 (TYK2), extracellular signal-regulated kinase (ERK) and STAT4, STAT5 and STAT6 were not potentiated by combinations of these cytokines, suggesting specificity for increased STAT3 phosphorylation. In conclusion, two otherwise antagonizing cytokines co-operate in activated human lymphoblasts and Th1 cells, possibly via STAT3 as a converging signal. These data demonstrate that IL-4 can directly enhance human Th1 cell function independently of its known actions on antigen-presenting cells. These findings should be of importance for the design of cytokine-targeted therapies of human Th-cell-driven diseases.
authors.affiliation: Department of Medicine III, Institute for Clinical Immunology and Rheumatology, University of Erlangen-Nuremberg, Erlangen, Germany. Martin.Kriegel@yale.edu
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kriegel
authors.forename: Theresa
authors.initials: T
authors.lastname: Tretter
authors.forename: Norbert
authors.initials: N
authors.lastname: Blank
authors.forename: Martin
authors.initials: M
authors.lastname: Schiller
authors.forename: Christoph
authors.initials: C
authors.lastname: Gabler
authors.forename: Silke
authors.initials: S
authors.lastname: Winkler
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Kalden
authors.forename: Hanns-Martin
authors.initials: HM
authors.lastname: Lorenz
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology*; D010766:Phosphorylation; D010835:Phytohemagglutinins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects*; D013268:Stimulation, Chemical; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit; D010835:Phytohemagglutinins; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma