Leukemia inhibitory factor is produced by myelin‐reactive T cells from multiple sclerosis patients and protects against tumor necrosis factor‐α‐induced oligodendrocyte apoptosis

Vanderlocht, Joris; Hellings, Niels; Hendriks, Jerome J. A.; Vandenabeele, Frank; Moreels, Marjan; Buntinx, Mieke; Hoekstra, Dick; Antel, Jack P.; Stinissen, Piet

doi:10.1002/jnr.20781

Cited by 58 publications

(49 citation statements)

References 59 publications

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“…In a genetic study, no association was found between these DNA polymorphisms and the prevalence of MS [58].…”

Section: Leukaemia Inhibitory Factor (Lif)mentioning

confidence: 80%

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Is there a role for neurotrophins in the pathology of multiple sclerosis?

et al. 2007

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“…In a genetic study, no association was found between these DNA polymorphisms and the prevalence of MS [58].…”

Section: Leukaemia Inhibitory Factor (Lif)mentioning

confidence: 80%

“…Interestingly, a recent study revealed that myelin-specific T cell lines express LIF in vitro [58]. Since T cells and macrophages may also produce LIF in MS lesions in situ, infiltrating immune cells may also exert a protective effect on oligodendrocytes.…”

Section: Leukaemia Inhibitory Factor (Lif)mentioning

confidence: 99%

Is there a role for neurotrophins in the pathology of multiple sclerosis?

et al. 2007

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“…This is in contrast to LIF-overexpressing mice which are characterized by interconversion of thymic and lymph node morphologies (13). LIFR␤ is present in Ag-activated T cell blasts and LIF is produced by monocytes, macrophages, and also T cells (30,31), thus opening the possibility of paracrine actions. Yet, similar to previous studies (9,32), exogenous addition of LIF to MOG-primed T cell cultures does not have any additional effect on T cell proliferation and adoptive transfer of WT T cells in LIF Ϫ/Ϫ mice does not change the course of EAE.…”

Section: Discussionmentioning

confidence: 91%

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

Linker

Kruse

Israel

et al. 2008

The Journal of Immunology

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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-γ 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.

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“…In addition to these experiments, we also performed studies to compare the effects of IL-11 to those of LIF, another cytokine of the gp130 family that has previously been implicated in oligodendrocyte protection and myelin formation in rodent systems (Mayer et al, 1994;Gard et al, 1995;Butzkueven et al, 2002;Ishibashi et al, 2005;Vanderlocht et al, 2006). Primary human fetal oligodendrocyte-enriched cultures were treated at plating with 10 ng/ml recombinant IL-11 or LIF, and allowed to grow and mature as above before being fixed, stained, and analyzed.…”

Section: Il-11 Potentiates the Survival And Maturation Of Primary Hummentioning

confidence: 99%

Interleukin-11 Potentiates Oligodendrocyte Survival and Maturation, and Myelin Formation

Zhang¹,

Taveggia²,

et al. 2006

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Mechanisms that regulate oligodendrocyte survival and myelin formation are an intense focus of research into myelin repair in the lesions of multiple sclerosis (MS). Although demyelination and oligodendrocyte loss are pathological hallmarks of the disease, increased oligodendrocyte numbers and remyelination are frequently observed in early lesions, but these diminish as the disease course progresses. In the current study, we used a microarray-based approach to investigate genes regulating repair in MS lesions, and identified interleukin-11 (IL-11) as an astrocyte-derived factor that potentiates oligodendrocyte survival and maturation, and myelin formation. IL-11 was induced in human astrocyte cultures by the cytokines IL-1␤ and TGF␤1, which are both prominently expressed in MS plaques. In MS tissue samples, IL-11 was expressed by reactive astrocytes, with expression particularly localized at the myelinated border of both active and silent lesions. Its receptor, IL-11R␣, was expressed by oligodendrocytes. In experiments in human cultures in vitro, IL-11R␣ localized to immature oligodendrocytes, and its expression decreased during maturation. In cultures treated with IL-11, we observed a significant increase in oligodendrocyte number, and this was associated with enhanced oligodendrocyte survival and maturation. Importantly, we also found that IL-11 treatment was associated with significantly increased myelin formation in rodent CNS cocultures. These data are the first to implicate IL-11 in oligodendrocyte viability, maturation, and myelination. We suggest that this pathway may represent a potential therapeutic target for oligodendrocyte protection and remyelination in MS.

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Leukemia inhibitory factor is produced by myelin‐reactive T cells from multiple sclerosis patients and protects against tumor necrosis factor‐α‐induced oligodendrocyte apoptosis

Cited by 58 publications

References 59 publications

Is there a role for neurotrophins in the pathology of multiple sclerosis?

Is there a role for neurotrophins in the pathology of multiple sclerosis?

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

Interleukin-11 Potentiates Oligodendrocyte Survival and Maturation, and Myelin Formation

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