title: Interferon-β induces hepatocyte growth factor in monocytes of multiple sclerosis patients.
abstract: Interferon-β is a first-line therapy used to prevent relapses in relapsing-remitting multiple sclerosis. The clinical benefit of interferon-β in relapsing-remitting multiple sclerosis is attributed to its immunomodulatory effects on inflammatory mediators and T cell reactivity. Here, we evaluated the production of hepatocyte growth factor, a neuroprotective and neuroinflammation-suppressive mediator, by peripheral blood mononuclear cells collected from interferon-β--treated relapsing-remitting multiple sclerosis patients, relapsing remitting multiple sclerosis patients not treated with interferon-β, and healthy volunteers. Using intracellular flow cytometry analysis, increased production of hepatocyte growth factor was observed in circulating CD14(+) monocytes from patients undergoing long-term treatment with interferon-β versus untreated patients. Complementary in vitro studies confirmed that treatment with interferon-β induced rapid and transient transcription of the hepatocyte growth factor gene in CD14(+) monocytes and that intracellular and secreted monocytic hepatocyte growth factor protein levels were markedly stimulated by interferon-β treatment. Additional exploration revealed that "pro-inflammatory" (CD14(+)CD16(+)) monocytes produced similar levels of hepatocyte growth factor in response to interferon-β as "classical" (CD14(+)CD16(-)) monocytes, and that CD14(+) monocytes but not CD4(+) T cells express the hepatocyte growth factor receptor c-Met. Our findings suggest that interferon-β may mediate some of its therapeutic effects in relapsing-remitting multiple sclerosis through the induction of hepatocyte growth factor by blood monocytes by coupling immune regulation and neuroprotection.
authors.affiliation: Unit of Neuroimmunology and Multiple Sclerosis, Division of Neurology, Department of Clinical Neurosciences, Faculty of Medicine, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Molnarfi
authors.forename: Mahdia
authors.initials: M
authors.lastname: Benkhoucha
authors.forename: Kristbjörg
authors.initials: K
authors.lastname: Bjarnadóttir
authors.forename: Catherine
authors.initials: C
authors.lastname: Juillard
authors.forename: Patrice H
authors.initials: PH
authors.lastname: Lalive
mesh_terms: D000328:Adult; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013557:Switzerland
chemical_list: D017228:Hepatocyte Growth Factor; D016899:Interferon-beta; D019859:Proto-Oncogene Proteins c-met