Regulatory properties of polysaccharopeptide derived from Coriolus versicolor and its combined effect with ciclosporin on the homeostasis of human lymphocytes Cheuk-Lun Lee a , Pingping Jiang a , Wai-Hung Sit a , Xiatong Yang b and Jennifer Man-Fan Wan a a School of Biological Sciences, Kadoorie Biological Sciences Building, The University of Hong Kong, Pokfulam Road, Hong Kong SAR and b Institute of Microbiology and Immunology, Faculty of Life and Environmental Science, Shanghai Normal University, Shanghai, China Abstract Objectives Lymphocyte homoeostasis is essential in inflammatory and autoimmune diseases. In search of natural fungal metabolites with effects on lymphocyte homoeostasis, we recently reported that polysaccharopeptide (PSP) from Coriolus versicolor exhibited ciclosporin-like activity in controlling aberrant lymphocyte activation. This object of this study was to investigate its effect on lymphocyte homoeostasis. This was done by investigating the mechanistic actions of PSP in relation to ciclosporin by performing cell cycle and cell death analysis of human lymphocytes in vitro. Methods We investigated the effect of PSP in the presence and absence of ciclosporin on cell proliferation, cell cycle, cell death, immunophenotype and cell cycle regulatory proteins in human lymphocytes. Key findings The data showed that PSP exhibited homoeostatic activity by promoting and inhibiting the proliferation of resting and phytohaemagglutinin (PHA)-stimulated lymphocytes, respectively. PHA-stimulated lymphocytes exhibited G0/G1 cell cycle arrest that was accompanied by a reduction of cyclin E expression with PSP treatment. Both PSP and ciclosporin blocked the reduction of the CD4/CD8 ratio in stimulated lymphocytes. PSP did not induce cell death in human lymphocytes, but the suppression of the Fas- receptor suggested a protective role of PSP against extrinsic cell death signals. These homoeostatic effects were more potent with combined PSP and ciclosporin treatment than with either fungal metabolite alone. Conclusions Collectively, the results reveal certain novel effects of PSP in lymphocyte homoeostasis and suggest potential as a specific immunomodulatory adjuvant for clinical applications in the treatment of autoimmune diseases. Keywords ciclosporin; Coriolus versicolor; lymphocyte; polysaccharopeptide; proteoglycan Introduction Immune system homoeostasis requires a balance between activation and suppression so as to achieve normal immune responses. [1] The homoeostasis of the immune system has to be maintained such that it not only responds to infections but also stops self-damage. Immunoregulatory agents act by inducing the proliferation (by means of cell cycle control) or death (by means of apoptosis and necrosis) of particular cell types, and thus affect inflammatory and autoimmune diseases. Ciclosporin (CsA, cyclosporine) is an immunosuppressive agent derived from the fungus Tolypocladium inflatum that has gained clinical application in inflammatory and autoimmune disorders. [2,3] The immune suppression mechanisms of ciclosporin involves its binding to calcineurin to prevent the activation of the nuclear factor of activated T cells (NFAT), which inhibits the subsequent activation of the inflammatory effectors. [4] However, despite its therapeutic benefit, long-term application of ciclosporin is associated with severe side effects and toxicity. [5,6] Current attempts are underway to reduce the dose of ciclosporin and attain therapeutic efficacy by using immunomodulatory adjuvants. [7–9] Research Paper JPP 2010, 62: 1028–1036 © 2010 The Authors Journal compilation © 2010 Royal Pharmaceutical Society of Great Britain Received January 9, 2010 Accepted April 12, 2010 DOI 10.1211/jpp.62.08.0009 ISSN 0022-3573 Correspondence: Dr Jennifer Man-Fan Wan, School of Biological Sciences, Kardoorie Biological Science Building, The University of Hong Kong, Hong Kong, China. E-mail: jmfwan@hkusua.hku.hk 1028