The cytokine interleukin-10 (IL10) is the major negative regulator of immune and hemopoietic cell function. Loss of the normal IL10 signalling has been associated with human inflammatory disorders and hematological malignancies. Research in our lab is directed at characterizing the molecular signaling pathways utilized by IL10 in its target cells. Understanding these pathways provide insight into how IL10 works and also support the development of therapeutic strategies that mimic the beneficial effects of IL10.
Our discovery that the inositol phosphatase SHIP mediates the early, immediate effect of IL10 is an example of our translation of basic research findings to potential clinical application. Because of SHIP’s importance in suppressing immune cell function we developed a high-throughput SHIP enzyme assay and screened for small molecule activators of SHIP activity. We found that molecules belonging to the Pelorol family activated SHIP. SHIP activators are predicted to inhibit inflammatory cell activation and we found that Pelorol and analogues indeed inhibited inflammation in both cell and animal models of inflammatory disease. Pelorol and analogues are now being developed for treatment of inflammatory disorders and hematological malignancies by a UBC spin-off company. Another important outcome from our discovery of small molecule SHIP agonists is the finding that SHIP is an allosterically activated enzyme, and that two hitherto unrecognized domains in SHIP mediates this activation. Studies are now continuing in collaboration with Dr. Lawrence MacIntosh’s lab to use NMR spectroscopy to characterize the nature of the interaction of Pelorol with these SHIP domains. Structure function studies are also underway to determine the effect of mutation or deletion of these domains on SHIP regulation of intracellular signaling pathways and overall biological outcome.
Other research programs in the lab include characterization of the miRNA/mRNA networks within cells in response to activation or transformation. We are also involved in the use of genomic strategies to identify biomarkers of inflammatory disease and cancer.
Ong CJ, Ming-Lum A, Nodwell M, Ghanipour A, Yang L, Williams DE, Kim J, Demirjian L, Qasimi P, Ruschmann J, Cao LP, Ma K, Chung SW, Duronio V, Andersen RJ, Krystal G, Mui AL.
Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood. 2007 Sep 15;110(6):1942-9.
Qasimi P, Ming-Lum A, Ghanipour A, Ong CJ, Cox ME, Ihle J, Cacalano N, Yoshimura A, Mui AL.
Divergent mechanisms utilized by SOCS3 to mediate interleukin-10 inhibition of tumour necrosis factor alpha and nitric oxide production by macrophages.
J Biol Chem. 2006 Mar 10;281(10) 6316-24.
Wei SW, Ming-Lum, A, Liu, Y , Wallach , D, Moore , KW, Mui, ALF.
Proteasome-mediated proteolysis of the Interleukin-10 receptor is important for signal downregulation.
J Interferon Cytokine Res. 2006 May;26(5):281-90
O’Farrell AM, Parry DA, Zindy F, Roussell M, Lees E, Moore KW and Mui ALF.
Inhibition of proliferation by IL-10 is mediated by Stat3-dependent induction of p19 INK4d .
J. Immunol. 164(9):4607-15, 2000
O’Farrell A-M, Liu Y, Moore KW and Mui ALF.
IL10 inhibits macrophage activation and proliferation by distinct signalling pathways: evidence for Stat3-dependent and -independent mechanisms.
EMBO J 17(4): 1006-1018, 1998