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Compound A, a Plant Origin Ligand of Glucocorticoid Receptors, Increases Regulatory T Cells and M2 Macrophages to Attenuate Experimental Autoimmune Neuritis with Reduced Side Effects

Institute of Brain Research, University of Tuebingen, Tuebingen, Germany

Experimental autoimmune neuritis (EAN) is a helper T cell-mediated autoimmune demyelinating inflammatory disease of the peripheral nervous system and serves as the animal model for human inflammatory demyelinating polyneuropathies. Compound A, a plant-derived phenyl aziridine precursor, was reported to activate glucocorticoid receptors to exert transrepression but not transactivation properties. In this study, we investigated the effects of Compound A in EAN rats. Compound A greatly suppressed paraparesis in EAN, even when administrated after the appearance of the first neurological signs. Accumulation of macrophages and lymphocytes, demyelination, and mRNA levels of inflammatory molecules in sciatic nerves of EAN were greatly attenuated by Compound A. In addition, Compound A inhibited progression of neuropathic pain and repressed microglia but not astrocyte activation and IL-1β and TNF- up-regulation in EAN spinal cords. In EAN sciatic nerves, Compound A treatment increased numbers of anti-inflammatory M2 macrophages. Furthermore, Compound A induced the switch of macrophages from inflammatory M1 type to anti-inflammatory M2 type in vitro. In lymph nodes of EAN rats, Compound A depressed Th1 and Th17 cytokines, but increased Th2 cytokine and Foxp3 expression. An increase of Foxp3⁺/CD4⁺ regulatory T cells was seen in peripheral blood of EAN rats following Compound A treatment. In addition, Compound A did not cause a hyperglycemia effect in EAN rats as compared with the immunosuppressive steroid prednisolone. Therefore, our data demonstrated that Compound A could effectively suppress EAN with reduced side effects by attenuating inflammation, suggesting that Compound A could be a potent candidate for treatment of autoimmune neuropathies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Zhiren Zhang and Zhi-Yuan Zhang both contributed equally to this work.

² Address correspondence and reprint requests to Zhiren Zhang, Institute of Brain Research, University of Tuebingen, Calwer Street 3, D-72076 Tuebingen, Germany. E-mail address: zhangzhiren{at}yahoo.com

³ Abbreviations used in this paper: EAN, experimental autoimmune neuritis; PNS, peripheral nervous system; GBS, Guillain-Barre syndrome; iNOS, inducible nitric oxide synthase; GC, glucocorticoid; GR, glucocorticoid receptor; GRE, glucocorticoid response element; HWT, hind-paw withdrawal threshold; GFAP, glial fibrillary acidic protein; LFB, Luxol Fast Blue; TAT, tyrosine aminotransferase; PEPCK, phosphoenolpyruvate carboxykinase.