@article{6db2a4a6800c492b9dc0e4fc4d2f1621,
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.",
keywords = "Cytokine, Fibroblasts, IL1b, IL6, Inflammation, Lipid metabolism, Major depressive disorder, Mitochondrial function, Oxidative stress, TNFa",
author = "Money, {Kelli M.} and Zita Olah and Zeljka Korade and Garbett, {Krassimira A.} and Shelton, {Richard C.} and Karoly Mirnics",
note = "Funding Information: The studies were supported by R01 MH079299 ( NIMH ) to KM and R01 MH073630 to RS. KMM's work was also supported by Public Health Service award T32 GM07347 from the National Institute of General Medical Studies for the Vanderbilt Medical-Scientist Training Program. ZO's work was supported by the Vanderbilt International Scholar Program (VISP) Short-Term Fellowship and the Campus Hungary Fellowship B2/1SZ613229 . Part of the research in this publication was also supported by the Neurosciences Core of the VKC, funded by the EKS NICHD of the NIH under Award # U54HD083211 . The authors declare no conflict of interest related to the performed work. RS has been a consultant for Allergan (Forest Pharmaceuticals), Bristol-Myers Squibb Company, Cerecor, Inc., Clintara, LLC, Forest Pharmaceuticals, Janssen Pharmaceutica, Medtronic, Inc., MSI Methylation Sciences, Inc., Naurex, Inc., Nestle' Health (Pamlab, Inc.), Pfizer, Inc., Ridge Diagnostics, Shire Plc, Takeda Pharmaceuticals and has received grant support from Alkermes, Inc., Allergan (Forest Pharmaceuticals), Assurex Health, Avanir Pharmaceuticals, Cerecor, Inc., Genomind, Janssen Pharmaceutica, Naurex Inc., Nestle' Health (Pamlab, Inc.), Novartis Inc., Otsuka Pharmaceuticals, and Takeda Pharmaceuticals. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies. Funding Information: The studies were supported by R01 MH079299 (NIMH) to KM and R01 MH073630 to RS. KMM''s work was also supported by Public Health Service award T32 GM07347 from the National Institute of General Medical Studies for the Vanderbilt Medical-Scientist Training Program. ZO''s work was supported by the Vanderbilt International Scholar Program (VISP) Short-Term Fellowship and the Campus Hungary Fellowship B2/1SZ613229. Part of the research in this publication was also supported by the Neurosciences Core of the VKC, funded by the EKS NICHD of the NIH under Award #U54HD083211. The authors declare no conflict of interest related to the performed work. RS has been a consultant for Allergan (Forest Pharmaceuticals), Bristol-Myers Squibb Company, Cerecor, Inc., Clintara, LLC, Forest Pharmaceuticals, Janssen Pharmaceutica, Medtronic, Inc., MSI Methylation Sciences, Inc., Naurex, Inc., Nestle'' Health (Pamlab, Inc.), Pfizer, Inc., Ridge Diagnostics, Shire Plc, Takeda Pharmaceuticals and has received grant support from Alkermes, Inc., Allergan (Forest Pharmaceuticals), Assurex Health, Avanir Pharmaceuticals, Cerecor, Inc., Genomind, Janssen Pharmaceutica, Naurex Inc., Nestle'' Health (Pamlab, Inc.), Novartis Inc., Otsuka Pharmaceuticals, and Takeda Pharmaceuticals. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = may,
day = "1",
doi = "10.1016/j.nbd.2016.01.015",
language = "English (US)",
volume = "89",
pages = "46--54",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",
}