Background
Bipolar disorder (BD) is a serious and insistent psychiatric disorder resulting in substantial morbidity and mortality. Among several theories for describing the principal patho-etiology of this disorder, immune dysfunction has extensively attained attention of researchers [
1]. Comorbidity of BD with inflammatory diseases, dysregulation of cytokine levels in both peripheral blood and central nervous system (CNS) of patients and relapsing-remitting nature of disease are some clues that pointed out the significance of immune responses in the pathogenesis of BD [
1]. Tumor necrosis factor-α (TNF-α) and soluble tumor necrosis factor receptor type 1 (sTNF-R1) are among cytokines whose levels have been consistently higher in manic patients compared with both healthy individuals and euthymic patients [
2].
Suppressor of cytokine signaling (SOCS) proteins are the crucial negative regulators of immune responses that exert their effects through inhibiting the Jak/Stat signaling pathway [
3]. Eight members of this family have been identified in human among them are SOCS1 and SOCS3 which alter immune responses in microglia/monocytes and astrocytes as well [
4]. These two members of SOCS family are also involved in the TNF-α mediated function and signaling pathways [
5,
6]. The role of
SOCS genes in the pathogenesis of inflammatory diseases has been emphasized by the observed down-regulation of
SOCS1 and
SOCS5 genes in peripheral blood of multiple sclerosis (MS) patients [
7]. However, we have recently assessed expression of
SOCS genes in the peripheral blood of autistic patients and found no remarkable difference in their expression levels between patients and controls [
8]. Based on the role of SOCS proteins in the regulation of immune responses and the observed dysregulation of immune system in BD, we hypothesized that expression of these genes are dysregulated in patients with BD. Consequently, in the present project, we examined expression levels of these genes in peripheral blood of BD patients to unravel if their transcript levels are different between patients and controls and whether they can be used as diagnostic biomarkers to differentiate BD from healthy status.
Discussion
In the current study, we evaluated expression of
SOCS genes in the peripheral blood of BD patients. Based on the previously reported interactions between SOCS proteins and sex steroids [
10], we performed sex difference analysis as well. We found a sexual dimorphism in up-regulation of
SOCS genes except for
SOCS5 which was up-regulated in both male and female patients compared with the corresponding control subjects. Although SOCS proteins have been primarily recognized for their anti-inflammatory functions, they might have different functions based on the tissue in which they are expressed. For instance, SOCS3 expression in neurons repressed insulin growth factor-1 (IGF-1)-induced neurite outgrowth [
11] and reversed the neuroprotective effect of IGF-1 against TNF-α induced apoptosis [
12]. Consistent with these functions, elevated levels of SOCS3 in oligodendrocytes and neurons after traumatic brain damage might exert harmful effects [
13]. A previous study has shown decreased neurite mass in neuronal cell cultures being treated with serum of BD patients [
14]. Although the underlying mechanism of such in vitro observation is not known, this study indicates the presence of specific peripheral factors that might affect central tissues of BD patients. Patel et al. have previously suggested that temporary or insistent disturbance of blood brain barrier (BBB) integrity would lead to diminished CNS defense and higher permeability of proinflammatory elements from the peripheral blood into the brain. These happenings might be involved in the pathogenesis of BD [
15]. Higher levels of
SOCS genes expression in peripheral blood of BD patients might affect integrity of BBB or might lead to higher levels of these genes in CNS tissue due to malfunctioned BBB in BD patients. Alternatively, the observed over-expression of
SOCS genes in peripheral blood of male BD patients compared with healthy males might reflect higher levels of these genes in central tissues of BD patients as a result of a global event that modulate expression of these genes in whole tissues. On the other hand, such peripheral over-expression of
SOCS genes might be a compensatory mechanism to alleviate the detrimental effects of cytokine over-production in BD patients. The latter is supported by the observed role of SOCS1 up-regulation in suppression of TNF-α-mediated cell oxidative stress and apoptosis [
6].
Expression of SOCS proteins might also been related with levels of inflammatory markers. For instance, SOCS3 has an inhibitory effect on expression of IL-6 family cytokines [
16], but promotes expression of IL-10 [
17], an anti-inflammatory cytokine which is increased in serum samples of BD patients [
18]. Thus, a future perspective of our work is assessment of the relationship between serum inflammatory markers and SOCS expression in BD patients and also their variations between manic and depressive patients.
SOCS3 is also involved in the evolution of leptin resistance [
19]. Both leptin deficiency and leptin resistance might participate in changes in affective status [
20]. Consequently, the observed higher levels of
SOCS3 in peripheral blood of BD patients might lead to leptin resistance and contribute in the pathogenesis of BD through this axis. In addition, SOCS1 and SOCS3 proteins has been shown to induce insulin [
21], a condition that is associated with poor psychiatric outcomes in patients with BD [
22].
Expression levels of genes were not correlated with any of demographic or clinical parameters of study participants after adjustment for gender. In our previous study in autistic patients, we found correlation between
SOCS5 expression and age of patients, but such correlation was not detected in healthy subjects [
8]. However, contrary to the present study,
SOCS3 expression levels were significantly correlated with the age of all both patients and controls [
8]. Taken together, the correlation between expression of
SOCS genes and age not only depends on the disease status but is also determined by the age range. The latter is deduced from the difference in age range of study participants in our previous study versus the current study (children versus adults).
We also detected significant pairwise correlations between expression levels of
SOCS genes in both patients and controls which further supports our previous speculation regarding the presence of a single regulatory mechanism for these genes [
8].
Conclusion
We reported dysregulation of SOCS genes in BD. We also assessed diagnostic power of SOCS transcripts in BD and found superiority of SOCS5 as over other assessed genes. Notably, expression levels of this gene could differentiate euthymic patients from healthy subject with a diagnostic power of 0.92. Consequently, our data suggest suitability of this gene independence of patients’ signs or symptoms which potentiates it as a subsection of a panel of diagnostic biomarkers in BD in complicated situations such as in forensic medicine. However, future studies are needed to verify our results in larger sample sizes.
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