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Leukemia Inhibitory Factor Deficiency Modulates the Immune Response and Limits Autoimmune Demyelination: A New Role for Neurotrophic Cytokines in Neuroinflammation¹

Ralf A. Linker^2,*,, Niels Kruse^*, Stephanie Israel^*, Tao Wei, Silvia Seubert^*,, Anja Hombach^*, Bettina Holtmann, Fred Luhder^*, Richard M. Ransohoff, Michael Sendtner and Ralf Gold^*

^* Institute for Multiple Sclerosis Research, University of Goettingen and Gemeinnuetzige Hertie-Stiftung, Goettingen, Germany; Department of Neurology at St. Josef-Hospital Ruhr-University Bochum, Bochum, Germany; Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; and Institute for Clinical Neurobiology, Julius-Maximilians-Universität, Wuerzburg, Germany

The neurotrophic cytokines ciliary neurotrophic factor and leukemia inhibitory factor (LIF) play a key role in neuronal and oligodendrocyte survival and as protective factors in neuroinflammation. To further elucidate the potential of endogenous LIF in modulating neuroinflammation, we studied myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in LIF knockout mice (LIF^–/– mice). In the late phase of active myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, LIF^–/– mice exhibited a markedly milder disease course. The inflammatory infiltrate in LIF^–/– mice was characterized by an increase in neutrophilic granulocytes early and fewer infiltrating macrophages associated with less demyelination later in the disease. In good correlation with an effect of endogenous LIF on the immune response, we found an Ag-specific T cell-priming defect with impaired IFN- production in LIF^–/– mice. On the molecular level, the altered recruitment of inflammatory cells is associated with distinct patterns of chemokine production in LIF^–/– mice with an increase of CXCL1 early and a decrease of CCL2, CCL3, and CXCL10 later in the disease. These data reveal that endogenous LIF is an immunologically active molecule in neuroinflammation. This establishes a link between LIF and the immune system which was not observed in the ciliary neurotrophic factor knockout mouse.

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 This work was supported by the Deutsche Forschungsgemeinschaft, SFB 581, TPA1, the Institute for Multiple Sclerosis Research, University of Goettingen, Bereich Humanmedizin and Gemeinnuetzige Hertie-Stiftung, and the U.S. National Institutes of Health (RO1 NS 32151 to R.M.R.).

² Address correspondence and reprint requests to Dr. Ralf A. Linker, Department of Neurology, St. Josef-Hospital/Ruhr-University Bochum, Gudrunstrasse 56, D-44791 Bochum, Germany. E-mail-address: ralf.linker{at}rub.de

³ Abbreviations used in this paper: LIF, leukemia inhibitory factor; CNTF, ciliary neurotrophic factor; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; WT, wild type; bmDC, bone marrow dendritic cell; IP10, IFN--inducible protein 10.