title: Downregulation of class II antigen expression by FGF-heparin complexes is due primarily to heparin effect.
abstract: Fibroblast growth factors are thought to play a role in the pathogenesis of autoimmune inflammation. The evidence linking these growth factors to autoimmunity stems in part from their presence in mononuclear cells from inflammatory sites during disease processes. We sought to further dissect the mechanisms through which fibroblast growth factors might affect the inflammatory response. Peritoneal macrophages from autoimmune MRL 1pr/1pr mice and congenic wild-type MRL +/+ mice were cultured for 72 hours in the presence of either IFN-gamma, heparin, FGF-1, FGF-2, FGF-1 plus heparin, FGF-2 plus heparin or medium alone. Expression of MHC class II (I-Ak and I-Ek) antigens were analyzed using direct immunofluorescence and flow cytometry. As expected, at baseline there were higher numbers of I-Ak bearing cells in elicited peritoneal cells from 1pr mice relative to +/+ cells (70.8 +/- 14.9 versus 43.4 +/- 19.7, p = 0.046). Expression of I-Ak and I-Ek and percentage of I-E bearing cells were essentially the same between strains. Cells from 1pr and +/+ mice displayed reductions in the percentage of I-Ak expressing cells following culture with FGF-1 plus heparin and FGF-2 plus heparin. Similarly, cells from both 1pr and +/+ mice displayed significant reductions from baseline I-Ak expression following culture with FGF-1 and FGF-2 in the presence of heparin. Similar reductions were seen in cells from both strains cultured with heparin alone. No change from baseline was discernible when cells were cultured in the presence of FGF-1 or FGF-2 alone. Titration studies showed a maximum heparin effect at 5 units/ml culture. However, reduced amounts of heparin in the cell culture were directly proportional to decreased levels of I-Ak expression. These results suggest that cells from autoimmune MRL 1pr/1pr mice and wild type MRL +/+ mice respond similarly with a general reduction of I-Ak expression and a decrease in the percentage of I-Ak bearing cells in response to heparin with little discernible effect from addition of either FGF-1 or FGF-2. This change in class II expression suggests that the heparin-heparan component in FGF-heparin complexes may serve to downregulate class II expression during inflammation.
authors.affiliation: Department of Internal Medicine, Ohio State University, Columbus 43210, USA. hackshaw.1@osu.edu
authors.forename: K V
authors.initials: KV
authors.lastname: Hackshaw
authors.forename: R R
authors.initials: RR
authors.lastname: Lakshmanan
authors.forename: R W
authors.initials: RW
authors.lastname: Everett
authors.forename: C C
authors.initials: CC
authors.lastname: Fox
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D000949:Histocompatibility Antigens Class II / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D006801:Humans; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D019463:Mice, Inbred MRL lpr; D013045:Species Specificity
chemical_list: D000949:Histocompatibility Antigens Class II; D005346:Fibroblast Growth Factors; D006493:Heparin