title: An altered peripheral IL6 response in major depressive disorder.
abstract: 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.
authors.affiliation: Neuroscience Graduate Program, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Medical Scientist Training Program, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Money
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt International Scholar Program, Vanderbilt University, Nashville, TN 37232, USA; Department of Psychiatry, University of Szeged, 6725 Szeged, Hungary.
authors.forename: Zita
authors.initials: Z
authors.lastname: Olah
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Korade
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Krassimira A
authors.initials: KA
authors.lastname: Garbett
authors.affiliation: Department of Psychiatry, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Shelton
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: karoly.mirnics@vanderbilt.edu.
authors.forename: Karoly
authors.initials: K
authors.lastname: Mirnics
mesh_terms: D002478:Cells, Cultured; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism*; D020405:Dermis / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000378:metabolism; D015850:Interleukin-6 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D014409:Tumor Necrosis Factor-alpha
keywords: Cytokine; Fibroblasts; IL1b; IL6; Inflammation; Lipid metabolism; Major depressive disorder; Mitochondrial function; Oxidative stress; TNFa