Elsevier

Neuroscience

Volume 125, Issue 4, 2004, Pages 903-920
Neuroscience

Effects of adenoviral-mediated gene transfer of interleukin-10, interleukin-4, and transforming growth factor-β on the survival of axotomized retinal ganglion cells

https://doi.org/10.1016/S0306-4522(03)00398-1Get rights and content

Abstract

Nitric oxide, synthesized by reactive microglia and astrocytes has been implicated in promoting neuronal degeneration observed in many diseases and insults of the central nervous system. We have recently shown that inducible nitric oxide synthase is expressed by retinal glial cells following optic nerve transection and that inhibition of nitric oxide synthesis enhances the survival of injured retinal ganglion cells. Anti-inflammatory cytokines including interleukin-10 (IL-10), interleukin-4 (IL-4), and transforming growth factor-β (TGF-β) have been shown to prevent inducible nitric oxide synthase expression, and inhibit nitric oxide synthesis by microglia and astrocytes in culture.

In the present study, we examined the effects of adenoviral mediated gene transfer of anti-inflammatory cytokines on the survival of axotomized retinal ganglion cells. Intraocular administration of adenoviral vectors encoding interleukin-10 (Ad.IL-10) and interleukin-4 (Ad.IL-4) enhanced the survival of axotomized retinal ganglion cells at 14 days after axotomy. Adenoviral vectors encoding TGF-β (Ad.TGF-β) had no effect on retinal ganglion cell survival. Separate animals were pretreated by injection of Ad.IL-10 or Ad.IL-4 into the superior colliculus (s.c.), the major target of ganglion cells, 7 days prior to axotomy. S.c. administration of Ad.IL-10 or Ad.IL-4 significantly increased ganglion cell survival compared with intraocular injection. IL-10 and IL-4 gene transfer also reduced the density of infiltrating ED1 positive monocytes in the nerve fiber layer at 14 days postaxotomy. Ad.TGF-β increased the density of ED1 positive monocytes infiltrating the nerve fiber layer after axotomy. Vectors encoding IL-10 or IL-4 also decreased nitrotyrosine immunoreactivity in the inner retina at 7 days postaxotomy, suggesting that these cytokines protect retinal ganglion cells from peroxynitrite formation that results from nitric oxide synthesis by activated glial cells.

The present study has implications for the treatment of CNS injury and diseases that involve reactive microglia and astrocytes. Our results suggest that interleukin-10 and interleukin-4 may help prevent neurodegeneration caused by the activation of glial cells after CNS injury.

Section snippets

Optic nerve transection and retrograde labeling

Adult, female Sprague–Dawley rats (225–250 g; Charles River), that were free of common pathogens and housed in a Level B pathogen free environment, were used in all experiments. Animals were cared for according to the guidelines of the Canadian Council on Animal Care. All efforts were made to minimize animal suffering and to use only the number of animals necessary to produce reliable scientific data. Rats were anesthetized with i.p. injections of 7% chloral hydrate (420 mg/kg of body weight)

Transfection of retinal cells following intraocular or superior collicular injection of Ad.lacZ

The majority of transfected cells, after intraocular injection of Ad.lacZ, were Müller glial cells (Fig. 1a). Müller cell somata in the inner nuclear layer (INL) their radial processes that terminated in the inner limiting membrane and outer limiting membrane were β-gal positive. The transfection rate of retinal Müller cells after intraocular Ad.lacZ injection averaged to approximately 0.6%. Retinal NFL astrocytes were also transfected by intraocular Ad.lacZ injection (Fig. 1b); however, only

Discussion

In the present study we compared the effects of three anti-inflammatory cytokines, IL-10, IL-4, and TGF-β on the survival of axotomized RGCs. Our results demonstrate that prolonged delivery of IL-10 or IL-4 by gene transfer to the retina or retrograde transport from the s.c. enhances the survival of axotomized RGCs. We also showed that IL-10 or IL-4 gene transfer decreases the density of ED1 positive monocytes/macrophages in the NFL after optic nerve transection. Prolonged administration of

Acknowledgements

This work was supported by a Natural Sciences and Engineering Research Council of Canada operating grant OGP0171190 to A.K.B. P.D.K. is supported by a studentship from the Ontario Neurotrauma Foundation.

References (109)

  • J Gehrmann et al.

    Microgliaintrinsic immunoeffector cell of the brain

    Brain Res Rev

    (1995)
  • B Hauss-Wegrzyniak et al.

    Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer's disease

    Brain Res

    (1998)
  • R.P Hellendall et al.

    Differential regulation of cytokine-induced major histocompatibility complex class II expression and nitric oxide release in rat microglia and astrocytes by effectors of tyrosine kinase, protein kinase C, and cAMP

    J Neuroimmunol

    (1997)
  • A.A Hiester et al.

    Interleukin-4 is chemotactic for mouse macrophages

    Cell Immunol

    (1992)
  • J Hu et al.

    Amyloid-beta peptide activates cultured astrocytesmorphological alterations, cytokine induction and nitric oxide release

    Brain Res

    (1998)
  • A.A Hurwitz et al.

    Tumor necrosis factor alpha and transforming growth factor beta upregulate astrocyte expression of monocyte chemoattractant protein-1

    J Neuroimmunol

    (1995)
  • S Ito et al.

    Interleukin-10 inhibits expression of both interferon a

    Blood

    (1999)
  • M Johnstone et al.

    A central role for astrocytes in the inflammatory response to beta-amyloidchemokines, cytokines and reactive oxygen species are produced

    J Neuroimmunol

    (1999)
  • Y Kitamura et al.

    Interleukin-4-inhibited mRNA expression in mixed rat glial and in isolated microglial cultures

    J Neuroimmunol

    (2000)
  • P.D Koeberle et al.

    Effects of GDNF on retinal ganglion cell survival following axotomy

    Vision Res

    (1998)
  • P.D Koeberle et al.

    Nitric oxide synthase inhibition delays axonal degeneration and promotes the survival of axotomized retinal ganglion cells

    Exp Neurol

    (1999)
  • L.Y Kong et al.

    Protein tyrosine kinase inhibitors decrease lipopolysaccharide-induced proinflammatory cytokine production in mixed glia, microglia-enriched or astrocyte-enriched cultures

    Neurochem Int

    (1997)
  • S.C Lee et al.

    Induction of nitric oxide synthase activity in human astrocytes by interleukin-1 beta and interferon-gamma

    J Neuroimmunol

    (1993)
  • R Lucius et al.

    Postnatal retinal ganglion cells in vitroprotection against reactive oxygen species (ROS)-induced axonal degeneration by cocultured astrocytes

    Brain Res

    (1996)
  • Y Okuda et al.

    Expression of the inducible isoform of nitric oxide synthase in the central nervous system of mice correlates with the severity of actively induced experimental allergic encephalomyelitis

    J Neuroimmunol

    (1995)
  • D Paris et al.

    Inhibition of Alzheimer's beta-amyloid induced vasoactivity and proinflammatory response in microglia by a cGMP-dependent mechanism

    Exp Neurol

    (1999)
  • E Peltekian et al.

    Adenovirus-mediated gene transfer to the brain: methodological assessment

    J Neurosci Methods

    (1997)
  • V.H Perry et al.

    Microglia in retinae transplanted to the central nervous system

    Neuroscience

    (1989)
  • W Schmidt et al.

    Evidence for bidirectional changes in nitric oxide synthase activity in the rat striatum after excitotoxically (quinolinic acid) induced degeneration

    Neuroscience

    (1995)
  • L Taupenot et al.

    Chromogranin A triggers a phenotypic transformation and the generation of nitric oxide in brain microglial cells

    Neuroscience

    (1996)
  • A.A te Velde et al.

    Interleukin-4 (IL-4) inhibits secretion of IL-1 beta, tumor necrosis factor alpha, and IL-6 by human monocytes

    Blood

    (1990)
  • E.H Tran et al.

    Astrocytes and microglia express inducible nitric oxide synthase in mice with experimental allergic encephalomyelitis

    J Neuroimmunol

    (1997)
  • G Almer et al.

    Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis

    J Neurochem

    (1999)
  • B.H Anderton et al.

    Monoclonal antibodies show that neurofibrillary tangles and neurofilaments share antigenic determinants

    Nature

    (1982)
  • R.B Banati et al.

    Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease

    Mov Disord

    (1998)
  • R.M Beckstead et al.

    A direct projection from the retina to the intermediate gray layer of the superior colliculus demonstrated by anterograde transport of horseradish peroxidase in monkey, cat and rat

    Exp Brain Res

    (1983)
  • M Berkelaar et al.

    Axotomy results in delayed death and apoptosis of retinal ganglion cells in adult rats

    J Neurosci

    (1994)
  • J.R Bethea et al.

    Traumatic spinal cord injury induces nuclear factor-kappaB activation

    J Neurosci

    (1998)
  • C.F Brosnan et al.

    Reactive nitrogen intermediates in human neuropathology: an overview

    Dev Neurosci

    (1994)
  • H.S Chen et al.

    Open-channel block of N-methyl-d-aspartate (NMDA) responses by memantinetherapeutic advantage against NMDA receptor-mediated neurotoxicity

    J Neurosci

    (1992)
  • M.H Chun et al.

    Light and electron microscopical analysis of nitric oxide synthase-like immunoreactive neurons in the rat retina

    Vis Neurosci

    (1999)
  • A Cohen et al.

    Neurotrophin-4/5 (NT-4/5) increases adult rat retinal ganglion cell survival and neurite outgrowth in vitro

    J Neurobiol

    (1994)
  • V.L Dawson

    Nitric oxide: role in neurotoxicity

    Clin Exp Pharmacol Physiol

    (1995)
  • W.I de Boer et al.

    Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease

    Am J Respir Crit Care Med

    (1998)
  • C.J De Groot et al.

    Immunocytochemical characterization of the expression of inducible and constitutive isoforms of nitric oxide synthase in demyelinating multiple sclerosis lesions

    J Neuropathol Exp Neurol

    (1997)
  • M.R de Waal et al.

    Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytesan autoregulatory role of IL-10 produced by monocytes

    J Exp Med

    (1991)
  • A Di Polo et al.

    Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Muller cells temporarily rescues injured retinal ganglion cells

    Proc Natl Acad Sci USA

    (1998)
  • A Ding et al.

    Macrophage deactivating factor and transforming growth factors-beta 1 -beta 2 and -beta 3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma

    J Immunol

    (1990)
  • A Erroi et al.

    IL-1 and IL-6 release by tumor-associated macrophages from human ovarian carcinoma

    Int J Cancer

    (1989)
  • L.P Erwig et al.

    Initial cytokine exposure determines function of macrophages and renders them unresponsive to other cytokines

    J Immunol

    (1998)
  • Cited by (82)

    • Construction and analysis of mRNA, lncRNA, and transcription factor regulatory networks after retinal ganglion cell injury

      2022, Experimental Eye Research
      Citation Excerpt :

      Moreover, inhibition of apoptotic or inflammatory pathways showed limited success in axon regeneration but cannot fully restore visual function in mice. For instance, transcriptional downregulation of apoptotic genes (Fernandes et al., 2012; Lebrun-Julien and Di Polo, 2008), caspase inhibitors (Kermer et al., 1999; Sanchez-Migallon et al., 2016), and modification of inflammatory responses restrained RGC death after ONC (Huarte and Rinn, 2010; Koeberle et al., 2004; Nadal-Nicolas et al., 2016). Increasing evidence has shown that immunoinflammation and apoptosis play a central role RGC injury (Almasieh et al., 2012; Bessero and Clarke, 2010; Geyer and Levo, 2020; Wei et al., 2019).

    View all citing articles on Scopus
    View full text