Synoviocyte stimulation by the LFA-1-intercellular adhesion molecule-2-Ezrin-Akt pathway in rheumatoid arthritis.
In rheumatoid arthritis (RA), the synovium is infiltrated by mononuclear cells that influence the proliferation and activation of fibroblast-like synoviocytes (FLS) through soluble mediators as well as cell-to-cell contact. To identify receptor-ligand pairs involved in this cross-talk, we cocultured T cells with FLS lines isolated from synovial tissues from RA patients. Coculture with T cells induced phosphorylation of Akt (Ser(473)) and its downstream mediators, GSK-3alpha/GSK-beta, FoxO1/3a, and mouse double minute-2, and enhanced FLS proliferation. T cell-mediated phospho-Akt up-regulation was unique for FLS as no such effect was observed upon interaction of T cells with dendritic cells and B cells. Akt activation was induced by all functional T cell subsets independent of MHC/Ag recognition and was also found with other leukocyte populations, suggesting the involvement of a common leukocyte cell surface molecule. Akt phosphorylation, enhanced in vitro FLS proliferation, and enhanced FLS IL-6 production was inhibited by blocking Abs to CD11a and ICAM-2 whereas Abs to ICAM-1 had a lesser effect. Selective involvement of the LFA-1-ICAM-2 pathway was confirmed by the finding of increased ezrin phosphorylation at Tyr(353) that is known to be downstream of ICAM-2 and supports cell survival through Akt activation. CD28(-) T cells, which are overrepresented in RA patients, have high CD11a cell surface expression and induce Akt phosphorylation in FLS more potently than their CD28(+) counterparts. These findings identify ICAM-2 as a potential therapeutic target to inhibit FLS activation in RA, allowing for a more selective intervention than broad LFA-1 inhibition.
Singh
Karnail
K
Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA.
Colmegna
Inés
I
He
Xiaowen
X
Weyand
Cornelia M
CM
Goronzy
Jörg J
JJ
D000328:Adult; D000368:Aged; D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D040881:CD11a Antigen / Q000032:analysis / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018920:Coculture Techniques; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D000099149:Ezrin
D019138:Antibodies, Blocking; D015703:Antigens, CD; D040881:CD11a Antigen; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D015850:Interleukin-6; D016169:Lymphocyte Function-Associated Antigen-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000099149:Ezrin; C065289:ICAM2 protein, human