Abstract
Elevation of the proinflammatory cytokine IL-6 has been implicated in depression; however, the mechanisms remain elusive. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression post-transcriptionally. The lethal-7 (let-7) miRNA family was suggested to be involved in the inflammation process and IL-6 was shown to be one of its targets. In the present study, we report elevation of Il6 in the prefrontal cortex (PFC) of a genetic rat model of depression, the Flinders Sensitive Line (FSL) compared to the control Flinders Resistant Line. This elevation was associated with an overexpression of LIN28B and downregulation of let-7 miRNAs, the former an RNA-binding protein that selectively represses let-7 synthesis. Also DROSHA, a key enzyme in miRNA biogenesis was downregulated in FSL. Running was previously shown to have an antidepressant-like effect in the FSL rat. We found that running reduced Il6 levels and selectively increased let-7i and miR-98 expression in the PFC of FSL, although there were no differences in LIN28B and DROSHA expression. Pri-let-7i was upregulated in the running FSL group, which associated with increased histone H4 acetylation. In conclusion, the disturbance of let-7 family biogenesis may underlie increased proinflammatory markers in the depressed FSL rats while physical activity could reduce their expression, possibly through regulating primary miRNA expression via epigenetic mechanisms.
Highlights
In the past two decades, clinical evidence has linked inflammatory responses with psychiatric disorders including major depressive disorder (MDD).[1,2] Cytokines, chemical messengers between immune cells, have been shown to have an important role in mediating behavioral, neuroendocrine and neurochemical features of MDD.[3]
We found detectable levels of Lin28b mRNA but not of Lin28a (Ct435) expressed in the prefrontal cortex (PFC) of adult Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL)
Since the let-7 family is known to target Il6, the results suggest that the let-7 family dysregulation contributes to the overexpression of Il6 in the in adult rat PFC, suggesting that LIN28B is the major paralog in regulating let-7 synthesis in the PFC
Summary
In the past two decades, clinical evidence has linked inflammatory responses with psychiatric disorders including major depressive disorder (MDD).[1,2] Cytokines, chemical messengers between immune cells, have been shown to have an important role in mediating behavioral, neuroendocrine and neurochemical features of MDD.[3] Elevated levels of proinflammatory cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α) and IL-6 have been found in serum/plasma and cerebrospinal fluid of depressed patients, in the absence of comorbid medical illness;[4,5] the most consistent result being an increase in IL-6.5–7 In addition, stimulation of the immune system with lipopolysaccharide can elicit symptoms of depression in humans with no previous episodes of depression.[8,9] Several findings indicated that IL-6 has a pathophysiological role in depression, especially in patients who fail to respond to selective serotonin reuptake inhibitors.[6,10,11,12,13] Physical exercise has been shown to have antidepressant effects and to reduce the risk for elevated levels of proinflammatory markers.[14,15] accumulated evidence shows increased IL-6 in MDD, the mechanisms underlying these alterations have not been clarified
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