An altered peripheral IL6 response in major depressive disorder
Autor: | Krassimira A. Garbett, Richard C. Shelton, Zeljka Korade, Kelli M. Money, Zita Olah, Karoly Mirnics |
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Rok vydání: | 2015 |
Předmět: |
0301 basic medicine
Chemokine medicine.medical_treatment Interleukin-1beta Inflammation Disease Major depressive disorder behavioral disciplines and activities Article lcsh:RC321-571 03 medical and health sciences 0302 clinical medicine mental disorders medicine Humans SOCS3 Receptor lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Cells Cultured Depressive Disorder Major biology business.industry Interleukin-6 Tumor Necrosis Factor-alpha Gene Expression Profiling Dermis Fibroblasts medicine.disease Mitochondria Oxidative Stress 030104 developmental biology Cytokine Lipid metabolism Neurology Suppressor of Cytokine Signaling 3 Protein Immunology biology.protein Tumor necrosis factor alpha Female medicine.symptom Mitochondrial function business 030217 neurology & neurosurgery |
Zdroj: | Neurobiology of Disease, Vol 89, Iss, Pp 46-54 (2016) |
ISSN: | 1095-953X |
Popis: | Major depressive disorder (MDD) is one of the most prevalent major psychiatric disorders with a lifetime prevalence of 17%. Recent evidence suggests MDD is not only a brain dysfunction, but a systemic disease affecting the whole body. Central and peripheral inflammatory changes seem to be a centerpiece of MDD pathology: a subset of patients show elevated blood cytokine and chemokine levels that partially normalize with symptom improvement over the course of anti-depressant treatment. As this inflammatory process in MDD is poorly understood, we hypothesized that the peripheral tissues of MDD patients will respond differently to inflammatory stimuli, resulting in an aberrant transcriptional response to elevated pro-inflammatory cytokines. To test this, we used MDD patient- and control-derived dermal fibroblast cultures to investigate their response to an acute treatment with IL6, IL1β, TNFα, or vehicle. Following RNA isolation and subsequent cDNA synthesis, quantitative PCR was used to determine the relative expression level of several families of inflammation-responsive genes. Our results showed comparable expression of the tested genes between MDD patients and controls at baseline. In contrast, MDD patient fibroblasts had a diminished transcriptional response to IL6 in all the gene sets tested (oxidative stress response, mitochondrial function, and lipid metabolism). We also found a significant increase in baseline and IL6 stimulated transcript levels of the IL6 receptor gene. This IL6 receptor transcript increase in MDD fibroblasts was accompanied by an IL6 stimulated increase in induction of SOCS3, which dampens IL6 receptor signaling. Altogether our results demonstrate that there is an altered transcriptional response to IL6 in MDD, which may represent one of the molecular mechanisms contributing to disease pathophysiology. Ultimately we hope that these studies will lead to validation of novel MDD drug targets focused on normalizing the altered IL6 response in patients. |
Databáze: | OpenAIRE |
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