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.
Highlights
The recognition of multiple sclerosis (MS) as an inflammatory, demyelinating, and neurodegenerative disease of the CNS [1] emphasizes the necessity for therapeutic strategies to target inflammation and neurodegeneration simultaneously. [2] This can be accomplished with combination therapies or by applying molecules that are capable of targeting both pathogenic processes
We report that monocytes from RRMS patients exhibited a reduced ability to produce hepatocyte growth factor (HGF) when compared with healthy volunteers, and that monocytes from IFN–b– treated RRMS patients produced significantly higher levels of HGF
We investigated the role of IFN–b in HGF synthesis by monocytes, a primary cell target for immunomodulatory drugs in CNS autoimmunity
Summary
The recognition of multiple sclerosis (MS) as an inflammatory, demyelinating, and neurodegenerative disease of the CNS [1] emphasizes the necessity for therapeutic strategies to target inflammation and neurodegeneration simultaneously. [2] This can be accomplished with combination therapies or by applying molecules that are capable of targeting both pathogenic processes. In the search for single molecules combining these requirements, recent reports suggest that hepatocyte growth factor (HGF) is one such candidate [3,4]. [6] These data suggest that, by combining immunomodulatory and neuroprotective effects, HGF may be a promising mediator of the clinical benefit of IFN–b treatment in RRMS. We report that monocytes from RRMS patients exhibited a reduced ability to produce HGF when compared with healthy volunteers, and that monocytes from IFN–b– treated RRMS patients produced significantly higher levels of HGF.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
