Emeritus Professor Ian Young
Areas of expertise
- Respiratory Diseases 110203
- Signal Transduction 060111
- Allergy 110701
- Genetically Modified Animals 100104
- Cellular Immunology 110704
- Biochemistry And Cell Biology 0601
Research interests
My research interests centre on the cytokines interleukin-3 (IL-3), interleukin-5 (IL-5), and granulocyte-macrophage colony stimulating factor (GM-CSF), which have overlapping activities on hematopoietic cells. They appear to be primarily involved in inducible hematopoiesis in response to infections and in the pathogenesis of allergic and inflammatory diseases. In allergic responses, IL-3 and IL-5 play critical roles role in the expansion of basophils and eosinophils respectively. GM-CSF has an important role in macrophage differentiation.
Our initial work was on the cloning of mouse IL-3 and human IL-5 and the determination of cytokine gene structure and organization. Subsequently, we used IL-5-deficient mice to study the role of IL-5 and eosinophils in allergic inflammation in asthma and parasite infections and determined the mechanisms regulating IL-5 expression by human and mouse T cells. We next investigated the structural biology of cytokine receptor signalling. The X-ray structure of the human beta common receptor involved in IL-3, IL-5 and GM-CSF signalling was published in Cell in 2001. We showed that the receptor had a unique structure being an intertwined dimer before activation and that it possesses a novel ligand binding site involving domains 1 and 4 of the respective protein chains of the dimer. More recently, we have identified a second isoform of the IL-3 receptor and are currently characterizing the two modes of IL-3 receptor activation and signalling. We are also studying the role of transcription factors and microRNAs in cytokine-supported differentiation of myeloid progenitors to inflammatory cells and will use the knowledge gained to explore new ways of controlling inflammation in asthma. Overexpression of IL-3Ra occurs in AML and we will investigate if aberrant IL-3 signalling is important in AML pathogenesis. We are currently collaborating with the Fujian Medical University in China which is a centre for leukemia treatment.
Researcher's projects
Cytokine-driven allergic inflammation: characterization of two isoform-specific modes of IL-3 receptor activation and investigation of new receptor-associated signalling partners.
Targeting miRNA to inhibit leukocyte differentiation as a new anti-inflammatory approach to the treatment of asthma.
Publications
- Yao S, Young IG, Norton R et al, 2011, 'Murine interleukin 3: Structure, dynamics and conformation in solution', Biochemistry, vol 50, pp2464-77
- Mirza, S, Walker, A, Chen, J et al 2010, 'The Ig-like domain of human GM-CSF receptor α plays a critical role in cytokine binding and receptor activation', Biochemical Journal, vol. 426, no. 3, pp. 307-317.
- Mirza, S, Chen, J, Wen, B et al 2010, 'Two modes of β-receptor recognition are mediated by distinct epitopes on mouse and human interleukin-3', Journal of Biological Chemistry, vol. 285, no. 29, pp. 22370-22381.
- Mirza, S, Chen, J, Murphy, J et al 2010, 'The role of interchain heterodisulfide formation in activation of the human common β and mouse βIL-3 receptors', Journal of Biological Chemistry, vol. 285, no. 32, pp. 24759-24768.
- Murphy, J, Metcalf, D, Young, I et al 2010, 'A convenient method for preparation of an engineered mouse interleukin-3 analog with high solubility and wild-type bioactivity', Growth Factors, vol. 28, pp. 104-110.
- Murphy, J, Soboleva, T, Mirza, S et al 2008, 'Clarification of the role of N-glycans on the common beta-subunit of the human IL-3, IL-5 and GM-CSF receptors and the murine IL-3 beta-receptor in ligand-binding and receptor activation', Cytokine, vol. 42, no. 2, pp. 234-42.
- Wang, J & Young, I 2007, 'Eosinophilic inflammation: mechanisms regulating IL-5 transcription in human T lymphocytes', Allergy, vol. 62, no. 10, pp. 1131-8.
- Matthews, C, Shaw, J, Hooper Jones, J et al 2007, 'Expression and evolution of the mammalian brain gene Ttyh1', Journal of Neurochemistry, vol. 100, no. 3, pp. 693-707.
- Murphy, J & Young, I 2006, 'IL-3, IL-5, and GM-CSF Signaling: Crystal Structure of the Human Beta-Common Receptor', Vitamins and Hormones, vol. 74, no. 1, pp. 1-30.
- Wang, J, Shannon, M & Young, I 2006, 'A role for Ets1, synergizing with AP-1 and GATA-3 in the regulation of IL-5 transcription in mouse Th2 lymphocytes', International Immunology, vol. 18, no. 2, pp. 313-23.
- Carr, P, Conlan, F, Ford, S et al. 2006, 'An improved resolution structure of the human β common receptor involved in IL-3, IL-5 and GM-CSF signalling which gives better definition of the high-affinity binding epitope', Acta Crystallographica Section F: Structural Biology and Crystallization Communications, vol. 62, no. Pt 6, pp. 509-513.
- Murphy, J, Ford, S, Olsen, J et al 2004, 'Interleukin-3 Binding to the Murine βIL-3 and Human βc Receptors Involves Functional Epitopes Formed by Domains 1 and 4 of Different Protein Chains', Journal of Biological Chemistry, vol. 279, no. 25, pp. 26500-26508.
- Yang, M, Hogan, S, Mahalingam, S et al. 2003, 'Eotaxin-2 and IL-5 cooperate in the lung to regulate IL-13 production and airway eosinophilia and hyperreactivity', Journal of Allergy and Clinical Immunology, vol. 112, pp. 935-943.
- Murphy, J, Ford, S, Wiedemann, U et al. 2003, 'A Novel Functional Epitope Formed by Domains 1 and 4 of the Human Common beta -Subunit Is Involved in Receptor Activation by Granulocyte Macrophage Colony-stimulating Factor and Interleukin 5*', Journal of Biological Chemistry, vol. 278, no. 12, pp. 10572-10577.
- Foster, P, Hogan, S, Yang, M et al. 2002, 'Interleukin-5 and eosinphils as therapeutic targets for asthma', Trends in Molecular Medicine, vol. 8, no. 4, pp. 162-167.
- Campbell, H, Fountain, S, McLennan, I et al. 2002, 'Fliih, a Gelsolin-Related Cytoskeletal Regulator Essential for Early Mammalian Embryonic Development', Molecular and Cellular Biology, vol. 22, no. 10, pp. 3518-3526.
- Mattes, J, Yang, M, Mahalingam, S et al 2002, 'Intrinsic Defect in T Cell Production of Interleukin (IL)-13 in the Absence of Both IL-5 and Eotaxin Precludes the Development of Eosinophilia and Airways Hyperreactivity in Experimental Asthma', Journal of Experimental Medicine, vol. 195, no. 11, pp. 1433-1444.
- Foster, P, Mould, A, Yang, M et al. 2001, 'Elemental signals regulating eosinophil accumulation in the lung', Immunological Reviews, vol. 179, pp. 173-181.
- Yang, M, Hogan, S, Henry, P et al. 2001, 'Interleukin-13 Mediates Airways Hyperreactivity through the IL-4 Receptor-Alpha Chain and STAT-6 Independently of IL-5 and Eotaxin', American Journal of Respiratory Cell and Molecular Biology, vol. 25, pp. 522-530.
- Carr, P, Gustin, S, Church, A et al 2001, 'Structure of the Complete Extracellular Domain of the Common beta Subunit of the Human GM-CSF, IL-3, and IL-5 Receptors Reveals a Novel Dimer Configuration', Cell, vol. 104, pp. 291-300.
- Gustin SE , Church, A, Ford, S et al 2001, 'Expression, crystallization and derivatization of the complete extracellular domain of the βc subunit of the human lL-5, lL-3 and GM-CSF receptors', European Journal of Biochemistry, vol. 268, no. 10, pp. 2905-2911.
