Elsevier

Neuroscience

Volume 137, Issue 2, 2006, Pages 463-472
Neuroscience

Research paper
Molecular neuroscience
Oligodendrocytes exhibit selective expression of suppressor of cytokine signaling genes and signal transducer and activator of transcription 1 independent inhibition of interferon-gamma-induced toxicity in response to leukemia inhibitory factor

https://doi.org/10.1016/j.neuroscience.2005.09.022Get rights and content

Abstract

Multiple sclerosis is an autoimmune disease of the CNS that results in the death of oligodendrocytes, the myelinating cells of the CNS. Previous studies have indicated that the cytokine leukemia inhibitory factor prevents the cytotoxic effects of interferon-gamma on oligodendrocytes in vitro, and the death of oligodendrocytes in an animal model of multiple sclerosis. Members of a recently characterized family of proteins, the suppressors of cytokine signaling, have been demonstrated to mediate negative cross-talk between cytokines, with induction of suppressors of cytokine signaling proteins by one cytokine inhibiting the activity of a second. Here, we assess whether induction of members of the suppressors of cytokine signaling family could explain the antagonistic biological effects of leukemia inhibitory factor and interferon-gamma upon oligodendrocytes. It is found that leukemia inhibitory factor rapidly and strongly induces the expression of suppressors of cytokine signaling-3 in cultured rat oligodendrocytes, whereas interferon-gamma weakly induces the expression of both suppressor of cytokine signaling-1 and 3. Pre-treatment of oligodendrocytes with leukemia inhibitory factor does not prevent the subsequent phosphorylation of signal transducer and activator of transcription-1 by interferon-gamma indicating that the leukemia inhibitory factor inhibition of interferon-gamma toxicity in oligodendrocytes is mediated by a suppressor of cytokine signaling-3 independent mechanism.

Section snippets

Animals

Experiments were conducted in accordance with the National Health and Medical Research Council of Australia guidelines and in accordance with protocols approved by the Howard Florey Institute animal ethics committee. Sprague–Dawley rats were brought from the Australian Research Council (Adelaide, Australia). Every attempt was made to minimize the number of animals required and to minimize their suffering.

Isolation of primary oligodendrocyte progenitor cells

Primary rat oligodendrocyte precursor cells (OPCs) were isolated as previously described (

LIF and IFNγ have opposing effects on oligodendroglial viability

The responsiveness of primary cells to both LIF and INFγ was first confirmed at the level of cell survival. The treatment of cells with LIF resulted in an increase of 41.9% in the proportion of viable cells over a 48-hour period relative to control cultures (P<0.01). In contrast, treatment of cells with IFNγ over this period resulted in a 37.3% decrease in viability (P<0.05). The co-treatment of cells with LIF in addition to IFNγ was sufficient to block this cytotoxic effect of IFNγ, with

Discussion

The present study confirms previous reports that the cytokines LIF and IFNγ have broadly opposing effects on oligodendroglia, with LIF potentiating the survival and IFNγ promoting the death of these cells. Neither the pro-survival activity of LIF nor the pro-death effect of IFNγ predominated when the two cytokines were co-administered: in particular, the administration of LIF rescued IFNγ-treated cultures to near control levels of survival but these cultures still displayed lower viability than

Conclusion

In summary, our findings strongly suggest that the apparently antagonistic effects of LIF and IFNγ upon oligodendrocytes are not subserved by SOCS-mediated negative cross-talk. Instead, the results suggest that the LIF-mediated effect is an independent survival response, given that any potential interactions are downstream of STAT activation. Both cytokines are known to be released during CNS inflammation, with LIF produced by astrocytes (Banner et al., 1997) and IFNγ by infiltrating T cells (

Acknowledgments

This research was supported by the National Health and Medical Research Council of Australia and by The National Multiple Sclerosis Society of the USA.

References (53)

  • H. Shi et al.

    Suppressor of cytokine signaling 3 is a physiologic regulator of adipocyte insulin signaling

    J Biol Chem

    (2004)
  • M.M. Song et al.

    The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities

    J Biol Chem

    (1998)
  • Y.M. Tokumoto et al.

    Posttranscriptional regulation of p18 and p27 Cdk inhibitor proteins and the timing of oligodendrocyte differentiation

    Dev Biol

    (2002)
  • A.M. Turnley et al.

    Regulation of MHC molecules on MBP positive oligodendrocytes in mice by IFN-gamma and TNF-alpha

    Neurosci Lett

    (1991)
  • C.S. Zong et al.

    Mechanism of STAT3 activation by insulin-like growth factor I receptor

    J Biol Chem

    (2000)
  • C. Agresti et al.

    Synergistic stimulation of MHC class I and IRF-1 gene expression by IFN-gamma and TNF-alpha in oligodendrocytes

    Eur J Neurosci

    (1998)
  • T. Andrews et al.

    TNFalpha potentiates IFNgamma-induced cell death in oligodendrocyte progenitors

    J Neurosci Res

    (1998)
  • C.J. Auernhammer et al.

    Autoregulation of pituitary corticotroph SOCS-3 expressioncharacterization of the murine SOCS-3 promoter

    Proc Natl Acad Sci USA

    (1999)
  • K.D. Baerwald et al.

    Developing and mature oligodendrocytes respond differently to the immune cytokine interferon-gamma

    J Neurosci Res

    (1998)
  • B.A. Barres et al.

    Multiple extracellular signals are required for long-term oligodendrocyte survival

    Development

    (1993)
  • J. Bromberg et al.

    The role of STATs in transcriptional control and their impact on cellular function

    Oncogene

    (2000)
  • M. Buntinx et al.

    Cytokine-induced cell death in human oligodendroglial cell lines. IIAlterations in gene expression induced by interferon-gamma and tumor necrosis factor-alpha

    J Neurosci Res

    (2004)
  • M. Buntinx et al.

    Cytokine-induced cell death in human oligodendroglial cell lines: I. Synergistic effects of IFN-gamma and TNF-alpha on apoptosis

    J Neurosci Res

    (2004)
  • H. Butzkueven et al.

    LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival

    Nat Med

    (2002)
  • V.C. Calegari et al.

    Suppressor of cytokine signaling-3 provides a novel interface in the cross-talk between angiotensin II and insulin signaling systems

    Endocrinology

    (2005)
  • B.A. Croker et al.

    SOCS3 negatively regulates IL-6 signaling in vivo

    Nat Immunol

    (2003)

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