Extracellular survivin up-regulates adhesion molecules on the surface of leukocytes changing their reactivity pattern.
Rheumatoid arthritis (RA) is an autoimmune disease with joints as a principal target of inflammation. We have shown recently that the extracellular expression of the antiapoptotic protein survivin is associated with a destructive course of RA. Here, we address the potential impact of extracellular survivin on peripheral blood leukocytes (PBL). The binding of survivin to the surface of human PBL as well as the expression of adhesion molecules were assessed by FACS. The expression of adhesion molecules on leukocytes as a function of circulating survivin was analyzed in blood of 24 patients with RA and compared with eight healthy individuals. We show that extracellular survivin expresses immunomodulatory properties. It binds to the surface of the majority of granulocytes and a significant part of lymphocytes and monocytes inducing the activation of alpha-chains of beta-integrins and their ligand ICAM-1. Survivin-induced expression of alpha-chains of beta 2-integrins is regulated by p38 MAPK and PI-3K but not by the NF-kappaB signaling pathway. Clinical relevance of our findings is supported by the in vivo association of high circulating survivin levels with an increased expression of CD11c on monocytes and granulocytes in RA patients. The results of our study demonstrate that extracellular survivin affects the phenotype of leukocytes having a possible impact on homing of inflammatory cells during arthritis.
Mera
Simona
S
Department of Rheumatology and Inflammation Research, Guldhedsgatan 10, S-413 46 Göteborg, Sweden.
Magnusson
Mattias
M
Tarkowski
Andrej
A
Bokarewa
Maria
M
D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D018821:CD18 Antigens / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000187:drug effects* / Q000276:immunology; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D000077022:Survivin; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
C107489:BIRC5 protein, human; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D000077022:Survivin; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases