Therapeutic potential of LIF in multiple sclerosis Helena Slaets 1 , Jerome J.A. Hendriks 1 , Piet Stinissen 1 , Trevor J. Kilpatrick 2 and Niels Hellings 1 1 Hasselt University, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Diepenbeek, Belgium 2 Center for Neuroscience and Howard Florey Institute, University of Melbourne, VIC 3010, Australia Therapies for multiple sclerosis (MS) reduce the relapse rate but are unable to stop neurological decline. Here, we evaluate the potential of leukemia inhibitory factor (LIF) as a novel therapeutic in diseases with a neurodegener- ative and inflammatory component, such as MS. LIF, which can be a proinflammatory cytokine, can also mod- ulate the immune response in a beneficial way. Recent evidence demonstrates a crucial role of LIF in neuropro- tection and axonal regeneration as well as the preven- tion of demyelination. Finally, LIF is an important survival factor for stem cells and neuronal precursors. Therefore, we propose that LIF is a potential therapeutic candidate for MS. Neuroprotective therapies are needed for multiple sclerosis (MS) MS is the most common cause of nontraumatic neurological disability in North America and Europe. Most patients initially develop a relapsing–remitting form of the disease (RRMS), characterized by episodes of neurological disability followed by episodes of improvement. After 8 to 20 years, the majority of patients with RRMS develop secondary progres- sive MS. In this stage, patients usually suffer few if any attacks but accumulate neurological disability. Approxi- mately 15% of patients are diagnosed with primary progres- sive MS, which is characterized by a continuous neurological decline starting at disease onset. Unfortunately, there is no cure for MS. Ten years after being diagnosed, half of un- treated MS patients are unable to maintain employment or perform household chores, and 25 years after disease onset, 50% are nonambulatory [1]. Available therapies modulate the immune response to reduce disease activity but are unable to stop neurological decline. Therefore, MS patients would greatly benefit from the development of neuropro- tective treatments that can prevent demyelination and neurodegeneration or preferably restorative strategies that can promote remyelination and axonal regeneration. Interestingly, in MS lesions, macrophages and T cells secrete leukemia inhibitory factor (LIF) [2]. We propose that LIF is a good candidate to stop the neurological decline that MS patients inevitably face. LIF belongs to a family of neuropoietic cytokines that signal through a receptor complex consisting of gp130 and LIFRb (Figure 1) [3]. Although studies on the peripheral nervous system (PNS) have previously ascribed neuroprotective properties to this cytokine, its therapeutic potential during central nervous system (CNS) inflammation has long been a mat- ter of debate. Recent studies have shown that LIF can exert beneficial effects on MS lesion pathologies (Box 1). Here, we highlight the protective effects of LIF on neurons and oligodendrocytes as well as its immunomodulatory proper- ties that might make it suitable for the treatment of MS. In addition, we focus on its ability to promote regeneration and discuss the results of preclinical and clinical studies elucidating the therapeutic potential of LIF. LIF as part of the endogenous biological response to protect the CNS LIF is undetectable in the healthy nervous system, but its expression increases after different types of neuronal dis- tress, including nerve injury, ischemia, spinal cord injury, in MS lesions, in the hippocampus of patients with Alzhei- mer’s or Parkinson’s disease and after seizure [2,4–9]. It has therefore been hypothesized that the activation of LIF signaling is part of an endogenous neurobiological re- sponse that limits nerve injury. Indeed, LIF can protect neurons and oligodendrocytes from harmful insults. In this section, we discuss the ability of LIF to (i) mediate neuro- protection and induce axonal regeneration and (ii) to pro- tect against demyelination and enhance remyelination. Neuroprotection In the 1990s, neuroprotective activities were already as- cribed to LIF in the context of peripheral nerve injury [10,11]. More recent studies have shown that LIF is also an important survival factor in the CNS. For example, in vivo LIF treatment limits the neurological deficits caused by ischemic brain injury in rats [12] and intravitreal injection of LIF prevents photoreceptor cell death caused by light-induced oxidative damage in mice [13]. Because recombinant LIF protects neural cells from stress, in- creased expression of endogenous LIF in response to neu- ral damage might be part of a natural defense mechanism. Indeed, the lack of endogenous LIF in a mouse model of inheritable retinitis pigmentosa accelerates retinal degen- eration [14]. Further support for the hypothesis that LIF is part of an endogenous neuroprotective response comes from studies on ‘conditioning lesions’. Conditioning lesions are sublethal insults that switch neurons into a regenera- tive state and allow them to survive subsequent damage Opinion Corresponding author: Slaets, H. (leen.slaets@uhasselt.be). 1471-4914/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2010.08.007 Trends in Molecular Medicine, November 2010, Vol. 16, No. 11 493