title: Fibroblast-like synoviocytes from rheumatoid arthritis patients express functional IL-15 receptor complex: endogenous IL-15 in autocrine fashion enhances cell proliferation and expression of Bcl-x(L) and Bcl-2.
abstract: The hallmarks of rheumatoid arthritis (RA) are leukocytic infiltration of the synovium and expansiveness of fibroblast-like synoviocytes (FLS). The abnormal proliferation of FLS and their resistance to apoptosis is mediated, at least in part, by present in RA joints proinflammatory cytokines and growth factors. Because IL-15 exerts properties of antiapoptotic and growth factors, and is produced by RA FLS, we hypothesized that IL-15 participates in RA FLS activation. To test this hypothesis, we first examined whether RA FLS express chains required for high affinity functional IL-15R. Indeed, RA FLS express IL-15Ralpha at mRNA and protein levels. Moreover, we confirmed the presence of IL-2Rbeta and common gamma-chains. Interestingly, TNF-alpha or IL-1beta triggered significant elevation of IL-15Ralpha chain at mRNA and protein levels. Next, we investigated the effects of exogenous or endogenous IL-15 on Bcl-2 and Bcl-x(L) expression, FLS proliferation, and apoptosis. Exogenous IL-15 enhanced RA FLS proliferation and increased the level of mRNA-encoding Bcl-x(L). To test the role of endogenous IL-15 in the activation of RA FLS, an IL-15 mutant/Fcgamma2a protein exerting properties of specific antagonist to the IL-15Ralpha chain was used. We found that blocking IL-15 biological activities using this protein substantially reduced endogenous expression of Bcl-2 and Bcl-x(L), and RA FLS proliferation that was reflected by increased apoptosis. Thus, we have demonstrated that a distinctive phenotype of RA FLS, i.e., persistent activation, proliferation, and resistance to apoptosis, is related to the autocrine activation of IL-15Rs by FLS-derived IL-15.
authors.affiliation: Department of Pathophysiology and Immunology, Institute of Rheumatology, Warsaw, Poland.
authors.forename: Mariola
authors.initials: M
authors.lastname: Kurowska
authors.forename: Weronika
authors.initials: W
authors.lastname: Rudnicka
authors.forename: Ewa
authors.initials: E
authors.lastname: Kontny
authors.forename: Iwona
authors.initials: I
authors.lastname: Janicka
authors.forename: Magdalena
authors.initials: M
authors.lastname: Chorazy
authors.forename: Jacek
authors.initials: J
authors.lastname: Kowalczewski
authors.forename: Maria
authors.initials: M
authors.lastname: Ziółkowska
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ferrari-Lacraz
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
authors.forename: Włodzimierz
authors.initials: W
authors.lastname: Maśliński
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D019254:Genes, bcl-2; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000235:genetics*; D015398:Signal Transduction; D013583:Synovial Membrane / Q000276:immunology* / Q000473:pathology; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; C508024:IL15RA protein, human; D019409:Interleukin-15; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D051020:bcl-X Protein