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Interleukin‐4 supports interleukin‐12‐induced proliferation and interferon‐γ secretion in human activated lymphoblasts and T helper type 1 cells
Author(s) -
Kriegel Martin A.,
Tretter Theresa,
Blank Norbert,
Schiller Martin,
Gabler Christoph,
Winkler Silke,
Kalden Joachim R.,
Lorenz HannsMartin
Publication year - 2006
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/j.1365-2567.2006.02404.x
Subject(s) - tyrosine phosphorylation , janus kinase , cytokine , biology , stat4 , stat protein , tyrosine kinase 2 , microbiology and biotechnology , tyrosine kinase , signal transduction , lymphoblast , stat3 , cancer research , immunology , cell culture , stat , platelet derived growth factor receptor , growth factor , receptor , biochemistry , genetics
Summary Interleukin‐12 (IL‐12) and IL‐4 are known to differentially promote T helper (Th) cell differentiation. While IL‐12 induces interferon‐γ (IFN‐γ) 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 γ‐chain (γ 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‐α synthesis, enhanced IFN‐γ production, and shedding of soluble IL‐2 receptor α as expected. Importantly, combining IL‐4 with IL‐12 also enhanced IFN‐γ 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.