Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression

Abstract

Background: Interferon (IFN)-alpha has been used to study the effects of innate immune cytokines on the brain and behavior in humans. The degree to which peripheral administration of IFN-alpha accesses the brain and is associated with a central nervous system (CNS) inflammatory response is unknown. Moreover, the relationship among IFN-alpha-associated CNS inflammatory responses, neurotransmitter metabolism, and behavior has yet to be established.

Methods: Twenty-four patients with hepatitis C underwent lumbar puncture and blood sampling after approximately 12 weeks of either no treatment (n = 12) or treatment with pegylated IFN-alpha 2b (n = 12). Cerebrospinal fluid (CSF) and blood samples were analyzed for proinflammatory cytokines and their receptors as well as the chemokine, monocyte chemoattractant protein-1 (MCP-1), and IFN-alpha. Cerebrospinal fluid samples were additionally analyzed for monoamine metabolites and corticotropin releasing hormone. Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale.

Results: Interferon-alpha was detected in the CSF of all IFN-alpha-treated patients and only one control subject. Despite no increases in plasma IL-6, IFN-alpha-treated patients exhibited significant elevations in CSF IL-6 and MCP-1, both of which were highly correlated with CSF IFN-alpha concentrations. Of the immunologic and neurotransmitter variables, log-transformed CSF concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were the strongest predictor of depressive symptoms. Log-transformed CSF concentrations of IL-6, but not IFN-alpha or MCP-1, were negatively correlated with log-transformed CSF 5-HIAA (r(2) = -.25, p < .05).

Conclusions: These data indicate that a peripherally administered cytokine can activate a CNS inflammatory response in humans that interacts with monoamine (serotonin) metabolism, which is associated with depression.

Figure 1

CSF Immunologic Biomarkers in Control versus IFN-alpha/ribavirin-treated patients with HCV. Cerebrospinal fluid (CSF) samples for the assessment of relevant innate immune cytokines including interferon (IFN)-alpha (Panel A), interleukin (IL)-6 (Panel B) as well as the chemokine, monocyte chemoattractant protein 1 (MCP-1) (Panel C), were compared in control (n=12) and interferon (IFN)-alpha/ribavirin-treated (n=12) patients with hepatitis C virus (HCV) infection. IFN-alpha/ribavirin-treated subjects were studied after ~12 weeks on IFN-alpha/ribavirin therapy. CSF concentrations of IFN-alpha, IL-6 and MCP-1 were significantly elevated in IFN-alpha-treated subjects compared to controls (p<0.01).

Figure 2

Correlation between CSF IL-6 and 5-HIAA in Control and IFN-alpha/ribavirin-treated patients with HCV. Cerebrospinal fluid (CSF) samples for the assessment of interleukin (IL)-6 and the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were obtained from control (n=12) and interferon (IFN)-alpha/ribavirin-treated (n=12) patients with hepatitis C virus (HCV) infection. IFN-alpha/ribavirin-treated subjects were studied after ~12 weeks on IFN-alpha/ribavirin therapy. CSF immune and monoamine measures were log transformed (ln) to achieve normality. CSF lnIL-6 was found to significantly correlate with CSF ln5-HIAA (r=−0.50, df=24, p=0.013).