Head of Department
Royal Society Industrial Research Fellow
7 West 3.9 and 5W 2.45
Tel: +44 (0) 1225 383641 and +44 (0) 1225 384024
Prof Stephen Ward
Inflammatory Cell Biology Lab
Our research is geared toward understanding of the biochemical mechanisms that facilitate the process of inflammation. This is a beneficial host response to foreign challenge or tissue injury that leads ultimately to the restoration of tissue structure and function. Some diseases, such as rheumatoid arthritis, are driven by the inflammatory process. Others, such as sepsis syndrome, are due to inflammation contributing as much to the disease process as the provoking infectious agents, whilst yet others, such as hepatic cirrhosis, are due largely to a post-inflammatory fibrosis. The inflammatory response requires innate immunity and in some cases adaptive responses which are the two main integral components of the hosts’ defence system against invading pathogens. Innate immunity acts as a first line of defence against noxious material and can provide the necessary signals to instruct the adaptive immune system to mount a response. In turn, the adaptive immune response relies on the innate immune system to provide necessary effectors in the form of phagocytes and granulocytes to deal with the initiating stimulus.
My research focuses on PI3K and its role in the inflammatory process. Since the discovery of the prototypical PI3K in the late 1980’s, the family of PI3Ks and their lipid products (PI(3)P, PI(3,4)P2 and PI(3,4,5)P3 [PIP3]) have been the focus of intense investigation. Since the mid-1990’s I have used pharmacological and molecular approaches to identify the biochemical and physiological importance of PI3K-dependent-signalling pathways in the immune system. PI3Ks regulate important signalling cascade(s) involved in a plethora of cellular functional events such as survival, gene regulation, cell migration, growth and proliferation. My group is currently studying the activation of this signalling cascade during activation of the immune system. Specifically we are interested in the role that this molecule and its downstream biochemical and functional effectors play in key immune cells such as lymphocytes, macrophages, mast cells and eosinophils following activation by antigen, inflammatory mediators (e.g. chemokines and cytokines) and novel phospholipids immune regulators.
The Therapeutic Potential of our Work
Pharmacology has contributed greatly to the therapeutic tools currently used to treat a plethora of inflammatory diseases. It is sobering to realize that in spite of the diversity of these diseases, the number of drugs available to the clinician to treat inflammatory diseases is actually very limited. Drugs such as COX-2 inhibitors and synthetic glucocorticoids remain a mainstay in the treatment of many of these inflammatory diseases. Intense research activity over the past 20 years has revealed a whole host of potential targets, a most recent success being TNF, which can be inhibited with engineered soluble receptors or blocking humanized monoclonal antibodies. More successes are likely to follow and the important role of PI3K isoforms and chemokines in both innate and adaptive immunity suggests that selective inhibitors may be therapeutically useful in inflammatory and autoimmune disorders. In addition, there is also potential for the wider application of these inhibitors in other diseases such as thrombosis, cardiac disease and hypertension, so it is imperative that we understand the complexities and subtleties of this signalling pathway.
Use of bioprobes to analyse the spatio-temporal regulation of phospholipids during T cell migration and activation
Phosphoinositide 3-kinases (PI3Ks) phosphorylate phosphoinositide (PI) lipids at the 3'OH position of the inositol ring which in turn have been implicated in a plethora of biological events including migration and activation of lymphocytes. The main 3'-phosphorylated PI species found in mammalian cells after receptor stimulation are PI(3,4)P2 and PI(3,4,5)P3. The principle aim of my work is to visualise the spatio-temporal organisation of the major PI3K lipid products PI(3)P, PI(3,4)P2 and PI(3,4,5)P3 in T lymphocytes undergoing two distinct types of polarised response: (i) directional migration towards chemokines and (ii) stimulation of the T cell antigen receptor. This is acheived by using fluorescently-tagged (e.g. green fluorescent protein) lipid binding domains with specificity for PI(3)P, PI(3,4)P2 and PI(3,4,5)P3 (e..g. GFP-PKB PH domain) which have been stably transfected into T cell lines/human peripheral blood-derived T cells or which are transgenically expressed in murine T cells . To assess the role of individual PI3K isoforms in the accumulation of distinct PI lipids, isoforms are targeted by a combination of isoform-selective inhibitors, expression of gain-of/loss-of function mutants, as well as siRNA and use of isoform-selective gene knockout mice.
Chemokine receptor internalisation and trafficking
Another area of interest in my lab is the analysis of signaling pathways involved in the internalisation and recycling of chemokine receptors on the surface of leukocytes. Once again, we are using fluorescently-tagged proteins (e.g. receptors and signaling proteins such as PI3K and RabGTPAses) to monitor these events.
Toward understanding molecular and cellular basis of inflammatory bowel disease
The Inflammatory Bowel Diseases (IBD) are chronic relapsing and remitting disorders characterised by dysregulated intestinal inflammation. Tri-directional cytokine/chemokine signals between myofibroblasts, epithelial and T cells are involved in regulating immune activation in the gut.
My group is engaged in identifying cross-talk between these cells during the activation versus restitution stages of the inflammatory response. Specifically, we are addressing the role of a range of inflammatory mediators (including cytokines, chemokines and lipid chemoattractants) and their receptors in the regulation of recruitment, activation and function of these and other cells during intestinal immune response. Our studies are currently focused on characterising expression and function of inflammatory mediators and their receptors primarily in the large intestine (but also in the small intestine and elsewhere in the GI tract). Current interests include exploring the homing and role of circulating fibrocytes as well as resident myofibroblasts in wound healing and restitution of inflammation and investigating the role of mast cells as well as the Treg and ThIL-17 T cell subsets in the mucosal immune response. Our research is therefore very much orientated toward translation into a clinical setting and is therefore performed in close collaboration with clinicians at the Royal United Hospital, Bath.
Drug targets in lung transdifferentiation and airway disease
Transdifferentiation is defined as the conversion of one cell type to another. One example is the transformation of epithelial cells to fibroblasts (or myofibroblasts) (more commonly referred to as epithelial mesenchymal transition EMT). EMT is a key feature of several fibrotic interstitial lung diseases and is characterised by tissue remodelling, fibroproliferation and deposition of extracellular matrix in the lung parenchyma. The prototypical fibrotic lung disease is idiopathic pulmonary fibrosis (IPF), a progressive disorder that culminates in premature death from respiratory failure and in which no treatment intervention has been effective to date. The mechanisms underlying EMT in the lung are poorly understood but are believed to involve production of inflammatory cytokines and/or chemokines. We are presently engaged in identifying the molecular and cellular events in EMT and/or transdifferentiation in order to help identify new drug targets for future therapies for inflammatory Publications
Carter, E., Miron-Buchacra, G., Goldoni, S., Danahay, H., Westwick, J., Watson, M. L., Tosh, D. and Ward, S. G., 2014. Phosphoinositide 3-kinase alpha-dependent regulation of branching morphogenesis in murine embryonic lung:Evidence for a role in determining morphogenic properties of FGF7. PLoS ONE, 9 (12), e113555.
Ball, J., Archer, S. and Ward, S., 2014. PI3K inhibitors as potential therapeutics for autoimmune disease. Drug Discovery Today, 19 (8), pp. 1195-1199.
Carter, E., Lau, C. Y., Tosh, D., Ward, S. G. and Mrsny, R. J., 2013. Cell penetrating peptides fail to induce an innate immune response in epithelial cells in vitro:Implications for continued therapeutic use. European Journal of Pharmaceutics and Biopharmaceutics, 85 (1), pp. 12-19.
Foster, J. G., Carter, E., Kilty, I., Mackenzie, A. B. and Ward, S. G., 2013. Mitochondrial superoxide generation enhances P2X7R-mediated loss of cell surface CD62L on naïve human CD4+ T lymphocytes. The Journal of Immunology, 190 (4), pp. 1551-1559.
Harris, S. J., Ciuclan, L., Finan, P. M., Wymann, M. P., Walker, C., Westwick, J., Ward, S. G. and Thomas, M. J., 2012. Genetic ablation of PI3Kγ results in defective IL-17RA signalling in T lymphocytes and increased IL-17 levels. European Journal of Immunology, 42 (12), pp. 3394-3404.
Foster, J.G., Blunt, M.D., Carter, E. and Ward, S.G., 2012. Inhibition of PI3K signaling Spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies. Pharmacological Reviews, 64 (4), pp. 1027-1054.
Blunt, M.D. and Ward, S.G., 2012. Pharmacological targeting of phosphoinositide lipid kinases and phosphatases in the immune system:Success, disappointment, and new opportunities. Frontiers in Immunology, 3, 226.
Ward, S.G. and O'Neill, L.A., 2012. Spurs in the hunt for new immunomodulatory drug targets. Current Opinion in Pharmacology, 12 (4), pp. 439-443.
Blunt, M. D. and Ward, S. G., 2012. Targeting PI3K isoforms and SHIP in the immune system: new therapeutics for inflammation and leukemia. Current Opinion in Pharmacology, 12 (4), pp. 444-451.
Pauling, J. D., Shipley, J. A., Raper, S., Watson, M. L., Ward, S. G., Harris, N. D. and McHugh, N. J., 2012. Comparison of infrared thermography and laser speckle contrast imaging for the dynamic assessment of digital microvascular function. Microvascular Research, 83 (2), pp. 162-167.
Ward, S. G., 2012. Phosphoinositide 3-kinases and leukocyte migration. Current Immunology Reviews, 8 (2), pp. 154-160.
Dowden, J., Pike, R. A., Parry, R. V., Hong, W., Muhsen, U. A. and Ward, S. G., 2011. Small molecule inhibitors that discriminate between protein arginine N-methyltransferases PRMT1 and CARM1. Organic and Biomolecular Chemistry, 9 (22), pp. 7814-7821.
Ward, S. G., Westwick, J. and Harris, S., 2011. Sat-Nav for T cells: Role of PI3K isoforms and lipid phosphatases in migration of T lymphocytes. Immunology Letters, 138 (1), pp. 15-18.
Harris, S. J., Parry, R. V., Foster, J. G., Blunt, M. D., Wang, A., Marelli-Berg, F., Westwick, J. and Ward, S. G., 2011. Evidence that the lipid phosphatase SHIP-1 regulates T lymphocyte morphology and motility. The Journal of Immunology, 186 (8), pp. 4936-4945.
Korniejewska, A., McKnight, A. J., Johnson, Z., Watson, M. L. and Ward, S. G., 2011. Expression and agonist responsiveness of CXCR3 variants in human T lymphocytes. Immunology, 132 (4), pp. 503-515.
Willox, I., Mirkina, I., Westwick, J. and Ward, S. G., 2010. Evidence for PI3K-dependent CXCR3 agonist-induced degranulation of human cord blood-derived mast cells. Molecular Immunology, 47 (14), pp. 2367-2377.
Dowden, J., Hong, W., Parry, R. V., Pike, R. A. and Ward, S. G., 2010. Toward the development of potent and selective bisubstrate inhibitors of protein arginine methyltransferases. Bioorganic & Medicinal Chemistry Letters, 20 (7), pp. 2103-2105.
Korniejewska, A., Watson, M. L. and Ward, S. G., 2010. Analysis of CXCR3 and atypical variant expression and signalling in human T lymphocytes. In: Marelli-Berg, F. M. and Nourshargh, S., eds. T-Cell Trafficking.Vol. 606. Humana Press, pp. 125-147.
Parry, R. V., Harris, S. J. and Ward, S. G., 2010. Fine tuning T lymphocytes: A role for the lipid phosphatase SHIP-1. Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics, 1804 (3), pp. 592-597.
Sun, L. R., Zhong, J. L., Cui, S. X., Li, X., Ward, S. G., Shi, Y. Q., Zhang, X. F., Cheng, Y. N., Gao, J. J. and Qu, X. J., 2010. Modulation of P-glycoprotein activity by the substituted quinoxalinone compound QA3 in adriamycin-resistant K562/A02 cells. Pharmacological Reports, 62 (2), pp. 333-342.
Parry, R. V. and Ward, S. G., 2010. Protein arginine methylation: a new handle on T lymphocytes? Trends in Immunology, 31 (4), pp. 164-169.
Harris, S. J., Foster, J. G. and Ward, S. G., 2009. PI3K isoforms as drug targets in inflammatory diseases:Lessons from pharmacological and genetic strategies. Current Opinion in Investigational Drugs, 10 (11), pp. 1151-1162.
Colleypriest, B. J., Palmer, R. M., Ward, S. G. and Tosh, D., 2009. Cdx genes, inflammation and the pathogenesis of Barrett's metaplasia. Trends in Molecular Medicine, 15 (7), pp. 313-322.
Ward, S. G., 2009. Millipede-like lymphocyte crawling: feeling the way with filopodia. Immunity, 30 (3), pp. 315-317.
Wang, S. B., Cheng, Y. N., Cui, S. X., Zhong, J. L., Ward, S. G., Sun, L. R., Chen, M. H., Kokudo, N., Tang, W. and Qu, X. J., 2009. Des-gamma-carboxy prothrombin stimulates human vascular endothelial cell growth and migration. Clinical & Experimental Metastasis, 26 (5), pp. 469-477.
Ward, S. G. and Marelli-Berg, F. M., 2009. Mechanisms of chemokine and antigen-dependent T-lymphocyte navigation. Biochemical Journal, 418 (1), pp. 13-27.
Ward, S. G. and Mrsny, R. J., 2009. New insights into mechanisms of gastrointestinal inflammation and cancer. Current Opinion in Pharmacology, 9 (6), pp. 677-679.
Sun, L. R., Li, X., Cheng, Y. N., Yuan, H. Y., Chen, M. H., Tang, W., Ward, S. G. and Qu, X. J., 2009. Reversal effect of substituted 1,3-dimethyl-1H-quinoxalin-2-ones on multidrug resistance in adriamycin-resistant K562/A02 cells. Biomedicine & Pharmacotherapy, 63 (3), pp. 202-208.
Webb, A., Johnson, A., Fortunato, M., Platt, A., Crabbe, T., Christie, M. I., Watt, G. F., Ward, S. G. and Jopling, L. A., 2008. Evidence for PI-3K-dependent migration of Th17-polarized cells in response to CCR2 and CCR6 agonists. Journal of Leukocyte Biology, 84 (4), pp. 1202-1212.
Gao, F. J., Cui, S. X., Chen, M. H., Cheng, Y. N., Sun, L. R., Ward, S. G., Kokudo, N., Tang, W. and Qu, X. J., 2008. Des-gamma-carboxy prothrombin increases the expression of angiogenic factors in human hepatocellular carcinoma cells. Life Sciences, 83 (23-24), pp. 815-820.
Chen, M.-H., Cui, S.-X., Cheng, Y.-N., Sun, L.-R., Li, Q.-B., Xu, W.-F., Ward, S. G., Tang, W. and Qu, X.-J., 2008. Galloyl cyclic-imide derivative CH1104I inhibits tumor invasion through suppressing matrix metalloproteinase activity. Anti-Cancer Drugs, 19 (10), pp. 957-965.
Wang, S. B., Cheng, Y. N., Wang, F. S., Sun, L. R., Liu, C. H., Chen, G. J., Li, Y. H., Ward, S. G. and Qu, X. J., 2008. Inhibition activity of sulfated polysaccharide of Sepiella maindroni ink on matrix metalloproteinase (MMP)-2. Biomedicine & Pharmacotherapy, 62 (5), pp. 297-302.
Wright, K. L., Robertson, D. A. F., Moyer, M. P. and Ward, S. G., 2008. Long term cannabinoid receptor (CBI) blockade in obesity: Implications for the development of colorectal cancer. International Journal of Cancer, 122 (8), pp. 1920-1921.
Ward, S. G., 2008. New drug targets in inflammation: efforts to expand the anti-inflammatory armoury. British Journal of Pharmacology, 153, S5-S6.
Harris, S. J., Parry, R. V., Westwick, J. and Ward, S. G., 2008. Phosphoinositide lipid phosphatases: Natural regulators of phosphoinositide 3-kinase signaling in T lymphocytes. Journal of Biological Chemistry, 283 (5), pp. 2465-2469.