Other Cytokines

In addition to IFNy, other cytokines also display unexpected neuroprotective effects. For example, we have shown that interleukin-6 (IL-6) protects anterior horn neurons from death induced by Theiler's virus without altering the development of the normal antiviral humoral response or the development of normal viral titer (Pavelko et al., 2003).

Instead, we found that IL-6 protects anterior horn neurons, as well as NSC-34 motor neurons (Cashman et al., 1992), from death induced by viral infection via a direct neuropro-tective mechanism (Pavelko et al., 2003) (Fig. 16). This finding is in agreement with other reports that IL-6 promotes neurite outgrowth and survival of cultured enteric neurons (Schafer et al., 1999), and that IL-6 delays the progression of motor neuron disease in wobbler mice (Ikeda et al., 1996). Infection with a neurotropic coronavirus activated astrocytes to produce IL-6 (Sun et al., 1995), and we observed a similar upregulation in astrocytic expression of IL-6 after Theiler's virus infection (Pavelko et al., 2003) (Fig. 16). Therefore, we suggest that IL-6, normally considered to be an immune modulator during inflammation, signals to protect motor neurons from death, potentially in a manner analogous to ciliary neurotrophic factor (CNTF), a neurotrophic factor that also uses the gp130 signal transduction module (Pavelko et al., 2003; Ransohoff et al., 2002) (Fig. 16). The relevance of IL-6-mediated neuroprotection to MS remains to be delineated, but the concentrations of IL-6 receptor components are altered in the cerebrospinal fluid and serum of patients with MS (Padberg et al., 1999), suggesting that IL-6 signaling may be important to protect neurons during a demyelinating insult (Ransohoff et al., 2002).

A variety of other cytokines are also implicated in MS and animal models of MS, including TNFa (Arnett et al., 2001, 2003; Paya et al., 1990), CNTF (Linker et al., 2002), leukemia inhibitory factor (Butzkueven et al., 2002), onco-statin M (Repovic et al., 2003), IL-10 (Petereit et al., 2003), and IL-4 (Hulshof et al., 2002), and a number of these cytokines use the common gp130 signal transduction module described previously. However, the exact mechanism(s) via which these factors function in MS, and the role each may play in protection of axons and neurons from damage or death associated with demyelination, remains to be discovered. Likewise, numerous neurotrophic factors and cytokines are known to support the survival of neurons and axons, including nerve growth factor, brain-derived neu-rotrophic factor, neurotrophin-3, neurotrophin-4/5, glial cell line-derived neurotrophic factor, CNTF (Ransohoff et al., 2002; Sofroniew et al., 2001), insulin-like growth factor-1 (Kaspar et al., 2003), vascular endothelial growth factor (Lambrechts et al., 2003), hepatocyte growth factor (Sun et al., 2002), cardiotrophin-like cytokine/cytokine-like factor 1 (Forger et al., 2003; Ransohoff et al., 2002), and other immune cell-derived factors (Yin et al., 2003). The role of each of these factors in limiting neurological dysfunction in MS is unknown, but is likely to be important, both for understanding the pathophysiology of the disease and for designing appropriate therapeutic interventions (Ransohoff et al., 2002). Moreover, the complexity of interactions possible between these factors and between elements of the immune system is certainly a critical consideration (Bonini et al., 2003). Obviously, the most efficacious therapy will be one that displays exquisite sensitivity and specificity. We have proposed the use of growth factor-like natural autoan-tibodies to rapidly promote remyelination, and thereby protect axons from the deleterious effects of exposure to immune effectors.

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