Abnormal gene and protein expression of inflammatory cytokines in the postmortem brain of schizophrenia patients
Introduction
Immune function abnormalities have been implicated in the etiology and pathophysiology of schizophrenia (SZ). Several studies suggest that prenatal infections act as a risk factor for immune function alterations later in life, such as abnormal cytokine production and marked changes in cognitive and affective behaviors throughout the lifespan (Miller et al., 2013). Several other studies also reported increased microglial activation in SZ patients (Bayer et al., 1999, Schnieder and Dwork, 2011, Steiner et al., 2008).
Cytokines are major mediators of immune function and hence it is not surprising that cytokines have been widely studied in SZ. The suggestion that abnormalities of cytokines are associated with SZ is based on several lines of evidence. For example, the administration of cytokines, such as interferon (IFN)-γ, to rats and humans produces a syndrome known as ‘sickness behavior’ (Dantzer et al., 1999). The development of psychosis with IFN therapy have been generally observed and reported, as reviewed by Cheng et al. (2009) and by Crane et al. (2003). Also, the administration of cytokines to cancer patients is associated with side effects such as anxiety, depression, psychosis, mania and delirium (Capuron et al., 2001). That abnormalities of cytokines are associated with SZ is also supported by the findings that proinflammatory cytokines are abnormally expressed in the serum of SZ patients, as reviewed by Potvin et al. (2008) and by Zakharyan and Boyajyan (2014). The involvement of cytokines in SZ is also based on studies of behavioral effects after peripheral administration of cytokines (Cheng et al., 2009). However, it is not clearly understood if cytokine abnormalities are also present in the brain. Cytokines can either be synthesized in the brain or transported from the periphery (Dantzer et al., 2008). Therefore, it is quite possible that cytokine abnormalities may also be present in the brain and associated with the pathophysiology of SZ. The initial evidence that abnormalities of cytokines may be present in the brain is substantiated by the reports of abnormal levels of cytokines in the cerebrospinal fluid (CSF) of SZ patients (el-Mallakh et al., 1993, Garver et al., 1999, Garver et al., 2003, Soderlund et al., 2009).
Some studies suggest an abnormal expression of cytokines in the postmortem brain of patients with mood disorders and SZ (Fillman et al., 2013, Shelton et al., 2010, Volk et al., 2015). For example, Shelton et al. (2010) found abnormal expression of several proinflammatory cytokines in the postmortem brain (PFC) of depressed subjects. Dean et al. (2010) also reported abnormalities of soluble and membrane-bound tumor necrosis factor (TNF) in the postmortem brain of patients with major depressive disorders (MDD).
In light of this background, it was of interest to examine if alterations in inflammatory cytokines are present in the postmortem brain of SZ patients. Therefore, the aim of the present study was to examine mRNA and protein expression levels of inflammatory cytokines, such as TNF-α, interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-13, and lymphotoxin-A (LTA) in the PFC of SZ patients.
Section snippets
Subjects
The study was performed in the PFC (Brodmann area 9 [BA9] of 31 SZ patients (16 SZ suicide victims and 15 non-suicide SZ patients) and 24 NC subjects. Brain tissues were obtained from the Maryland Brain Collection at the Maryland Psychiatric Research Center, Baltimore, Maryland. Tissues were collected only after a family member gave informed consent. All tissues from NC and SZ subjects were grossly examined by experienced neuropathologists. Toxicology data were obtained by blood and urine
mRNA levels of inflammatory cytokines in the PFC of SZ and NC subjects
We determined the mRNA levels of TNF-α, LTA, IL-1β, IL-6, IL-8, IL-10, IL-13 and IL-1 receptor antagonist (IL-1RA) in the PFC of SZ patients. The results are shown in Fig. 1.
Discussion
In this study, we examined the role of inflammatory cytokines in the pathophysiology of SZ. We determined both the pro and anti-inflammatory cytokines in the PFC obtained from SZ patients and NC subjects. We observed that the protein and gene expression of TNF-α and IL-6 were significantly increased and those of IL-10 were significantly decreased in the PFC of SZ patients compared with NC subjects. In addition, only protein levels of IL-8 were significantly decreased and those of LTA were
Limitations
This study has several strengths. Although brain immune genes have been studied using Affymetrix assay in SZ postmortem brain, our study is probably the first to determine both protein and mRNA of pro- and anti-inflammatory cytokines in postmortem brain of SZ patients individually. The main limitation of this study is that many of the SZ patients were on neuroleptics or on other psychoactive drugs at the time of death. Thus, it is not clear if the observed differences in cytokine levels are due
Conclusion
In this study, we show that the protein and mRNA expression of proinflammatory cytokines, such as TNF-α and IL-6, are significantly increased and the levels of anti-inflammatory cytokine IL-10 are significantly decreased. We also report that the protein levels of another member of the TNF superfamily, known as LTA, are also increased in SZ patients. Since both TNF-α and LTA are involved in the prenatal clearance of toxoplasmosis in the brain, this study may suggest that the observed cytokine
Funding
This research was supported by a grant RO1 MH098554 (Dr. Pandey) from the National Institute of Mental Health, Rockville, MD. The funding source had no role in study design, collection, analysis and interpretation of data or the writing of the manuscript.
Conflict of interest statement
All authors declare that they have no financial interests or potential conflicts of interest related directly or indirectly to this work.
Acknowledgments
We thank Runa Bhaumik, Ph.D. for her help with the statistical analyses.
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2021, Neuroscience and Biobehavioral ReviewsCitation Excerpt :We have noted the lack of consistent evidence for activation of cytokine signaling in the large transcriptomic consortia studies in section 2.2. Although four individual studies (Fillman et al., 2013; Volk et al., 2015; Lanz et al., 2019; Pandey et al., 2018) have reported increased mRNA expression of various cytokines, most consistently IL-6, this was not confirmed by assays of protein (Lanz et al., 2019) and two studies report IL-6 expression correlated with duration of illness and with lifetime and current exposure to medication (Fillman et al., 2013; Zhang et al., 2016). Gandal et al. (2018a) identified an astroglial/NFkB co-experession module that was overexpressed in schizophrenia, autism, and bipolar disorder but it was not associated with GWAS risk variants.