Interleukin 9
(1994)
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- Authors
- Supervisors
- Van Snick, Jacques
- Abstract
- This thesis deals with the structural and functional characterization of IL-9 and its receptor. The identification of the human IL-9 cDNA was made possible by using the murine cDNA as a probe. The protein, that contains 144 amino acids and exhibits a 55% identity with its urine counterpart, was expressed in a baculovirus vector, yielding a protein capable of enhancing in vitro survival of human T cell lines. Further analysis if this T cell growth factor activity showed that resting T cells do not respond to IL-9, that most T cell clones and lines, whatever their phenotype, proliferate in the presence of IL-9, and that this ability to respond to IL-9 is highly restricted but the stage of activation of the cells. <BR> To study the mechanisms underlying the regulation of IL-9 expression, the murine and human IL-9 genes were cloned. Sequence analysis revealed that these genes consist of 5 exons spread over ∼4 kb of DNA and organized in a similar fashion on both species. The two genes exhibited a high degree of identity in the coding sequences and in the 5’ flanking regions, which contained various consensus motifs for the binding of transcription factors. The expression of IL-9 by human PBCM was studied at the RNA level. It was shown that IL-9 expression is restricted to activated T cells and is dependent on preliminary synthesis of IL-2. <BR> The murine IL-9 receptor cDNA was isolated by expression cloning in COS cells and screening with 125 I-labeled IL-9. This receptor is a 52 kDa protein containing a signal peptide and a typical transmembrane domain, and belongs to the hematopoietin receptor superfamily. Its expression in COS cells produced high affinity binding sites for IL-9 suggesting that other chains were not needed for the binding. The human homolog was isolated by cross-hybridization and its expression in murine cells was shown to confer responsiveness to human IL-9. <BR> To further analyse the biological activities of IL-9 in vivo, I took advantage of the cloning of the murine IL-9 gene to generate IL-9 transgenic mice. These mice constitutively expressed large amounts of IL-9 and were first used to investigate the activity of IL-9 in T cell development. IL-9 overexpression did not significantly interfere with the development. IL-9 overexpression did not significantly interfere with the development of lymphoid organs but resulted in the occurrence of thymic lymphomas in 7% of the transgenic animals. Moreover, injection of subliminal doses of a chemical mutagen induced lymphomas in all IL-9 transgenic but not in normal mice. This contrast between the lack activity on normal cells and a strong oncogenic potential is further illustrated by in vitro results showing that IL-9 promotes the proliferation of many chemically- or irradiation- induced thymic lymphomas while normal adult thymocytes do not respond to this cytokine
- Affiliations
Citations
Renauld, J.-C. (1994). Interleukin 9. https://hdl.handle.net/2078.5/245171