title: Misoprostol modulates cytokine expression through a cAMP pathway: Potential therapeutic implication for liver disease.
abstract: Dysregulated cytokine metabolism plays a critical role in the pathogenesis of many forms of liver disease, including alcoholic and non-alcoholic liver disease. In this study we examined the efficacy of Misoprostol in modulating LPS-inducible TNFα and IL-10 expression in healthy human subjects and evaluated molecular mechanisms for Misoprostol modulation of cytokines in vitro. Healthy subjects were given 14day courses of Misoprostol at doses of 100, 200, and 300μg four times a day, in random order. Baseline and LPS-inducible cytokine levels were examined ex vivo in whole blood at the beginning and the end of the study. Additionally, in vitro studies were performed using primary human PBMCs and the murine macrophage cell line, RAW 264.7, to investigate underlying mechanisms of misoprostol on cytokine production. Administration of Misoprostol reduced LPS inducible TNF production by 29%, while increasing IL-10 production by 79% in human subjects with no significant dose effect on ex vivo cytokine activity; In vitro, the effect of Misoprostol was largely mediated by increased cAMP levels and consequent changes in CRE and NFκB activity, which are critical for regulating IL-10 and TNF expression. Additionally, chromatin immunoprecipitation (ChIP) studies demonstrated that Misoprostol treatment led to changes in transcription factor and RNA Polymerase II binding, resulting in changes in mRNA levels. In summary, Misoprostol was effective at beneficially modulating TNF and IL-10 levels both in vivo and in vitro; these studies suggest a potential rationale for Misoprostol use in ALD, NASH and other liver diseases where inflammation plays an etiologic role.
authors.affiliation: Department of Internal Medicine, University of Louisville, United States; Department of Pharmacology & Toxicology, University of Louisville, United States. Electronic address: l0gobe01@louisville.edu.
authors.forename: Leila
authors.initials: L
authors.lastname: Gobejishvili
authors.affiliation: Department of Internal Medicine, University of Louisville, United States.
authors.forename: Smita
authors.initials: S
authors.lastname: Ghare
authors.affiliation: RK Gastroenterology & Hepatology, Coppell, TX, United States.
authors.forename: Rehan
authors.initials: R
authors.lastname: Khan
authors.affiliation: Department of Bioinformatics & Biostatistics, University of Louisville, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Cambon
authors.affiliation: Department of Internal Medicine, University of Louisville, United States.
authors.forename: David F
authors.initials: DF
authors.lastname: Barker
authors.affiliation: Department of Internal Medicine, University of Louisville, United States; Department of Pharmacology & Toxicology, University of Louisville, United States.
authors.forename: Shirish
authors.initials: S
authors.lastname: Barve
authors.affiliation: Department of Internal Medicine, University of Louisville, United States; Department of Pharmacology & Toxicology, University of Louisville, United States; VA Medical Center, Louisville, KY, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: McClain
authors.affiliation: Department of Internal Medicine, University of Louisville, United States; VA Medical Center, Louisville, KY, United States.
authors.forename: Daniell
authors.initials: D
authors.lastname: Hill
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced; D000818:Animals; D000897:Anti-Ulcer Agents / Q000009:adverse effects / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008107:Liver Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016595:Misoprostol / Q000009:adverse effects / Q000494:pharmacology*; D009325:Nausea / Q000139:chemically induced; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000897:Anti-Ulcer Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016595:Misoprostol; D016753:Interleukin-10; D000242:Cyclic AMP
keywords: CREB; ChIP; Inflammation; Liver disease; NFκB; cAMP