title: Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease.
abstract: Crohn's disease and ulcerative colitis, the two main types of inflammatory bowel disease (IBD), were reported to be associated with a variety of genetic polymorphisms. A subset of these polymorphisms was identified in both diseases and only three of them were found in primary sclerosing cholangitis (PSC). rs3197999 (Arg689Cys) located in the MST1 gene is one of the most convincingly replicated IBD/PSC-associated polymorphisms but its functional consequences have not been investigated, yet. We expressed both MST1 gene variants (Arg(689) (MSP(wt)) and Cys(689) (MSP(mut)) in a eukaryotic cell system and compared their stimulatory effects on macrophage-like THP-1 cells. Except for the rate of apoptosis that remained unchanged, MSP(mut) significantly increased the stimulatory effect of MSP (macrophage-stimulating protein) on chemotaxis and proliferation by THP-1 cells, indicating a gain of function associated with the Arg689Cys exchange. A broad set of evidence reported previously suggests that pro-inflammatory changes in macrophage function have a major role in the initiation of the inflammatory process in IBD and PSC. Therefore, the gain of function observed with rs3197999 in MST1 might provide a cellular mechanism for the consistent association of this polymorphism with an increased risk for IBD and PSC.
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Mainz, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Häuser
authors.forename: C
authors.initials: C
authors.lastname: Deyle
authors.forename: D
authors.initials: D
authors.lastname: Berard
authors.forename: C
authors.initials: C
authors.lastname: Neukirch
authors.forename: C
authors.initials: C
authors.lastname: Glowacki
authors.forename: J K
authors.initials: JK
authors.lastname: Bickmann
authors.forename: J J
authors.initials: JJ
authors.lastname: Wenzel
authors.forename: K J
authors.initials: KJ
authors.lastname: Lackner
authors.forename: H
authors.initials: H
authors.lastname: Rossmann
mesh_terms: D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002465:Cell Movement; D049109:Cell Proliferation; D002633:Chemotaxis; D015209:Cholangitis, Sclerosing / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006224:Cricetinae; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma