Potential Mechanisms Of The Cns Effects Of Cytokines

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There are a myriad of mechanisms by which cytokines can effect nervous system function. These include induction of secondary cytokines that affect neuronal function (Licinio, Kling, & Hauser, 1998), release of stress hormones that are known to cause mood and cognitive alterations (Meyers & Valentine, 1995), the development of autoimmune thyroid disease (Jones, Wadler, & Hupart, 1998), alterations of neurotransmitter function that are important in frontal-subcortical neuronal circuitry (Ho, Lu, Huo, Fan, Meyers, Tansey, Payne, & Levin, 1994), and possibly effects on cerebral endothelium (Meyers & Valentine, 1995). Additionally, most recent studies utilize recombinant cytokines. There is a recent report on the use of natural interferon in asymptomatic HIV-positive individuals that reported fewer side effects than is gener-

Table 3. Summary of preliminary prospective studies of IFN-a neurotoxicity

► 19/27 (70%) CML patients declined on one or more cognitive tests

► 17/20 (85%) CML patients experienced a significant increase in emotional distress

► 1/6 (17%) hepatitis patients experienced cognitive decline

► 1/6 (17%) hepatitis patients experienced increased depression

► Patients who experienced cognitive decline were not necessarily the same patients who reported increased mood disturbance ally observed (Mapou, Law, Wagner, Malone, & Skillman, 1996). This report utilized different methodologies and had limited patient follow-up. It is known that recombinant proteins expressed in host cells may have differences in their folding compared to the natural protein. Over-expression of recombinant proteins may also lead to altered post-translational modifications (e.g., acylation, glycosylation, phosphorylation) that may be important for biological activity. However, if there are any differences between natural and recombinant cytokines, they must be cryptic since the recombinant protein produces a biological response predictive of the natural protein.

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