title: Cyclosporin A blocks the expression of lymphotoxin alpha, but not lymphotoxin beta, in human peripheral blood mononuclear cells.
abstract: The 2 lymphotoxin subunits LTalpha (also called tumor necrosis factor beta [TNF-beta]) and LTbeta belong to the family of TNF-related cytokines. They form either a soluble homotrimeric ligand (LTalpha(3)) that binds to and signals through CD120a/b (TNFRp55 and TNFRp75), or a membrane-associated heterotrimeric ligand (LTalpha(1)beta(2)) that binds to and signals through the LTbeta receptor (LTbetaR). In mice, LTbetaR signaling is critical for the maintenance of peripheral lymphoid tissues and optimal immune responses, and its down-regulation results in immunodeficiency. To determine the possible relationship between LT-mediated immunodeficiency and the immunosuppressive effects of cyclosporin A (CsA), we tested the effects of CsA on the expression of LTalpha and LTbeta in human peripheral blood mononuclear cells (PBMCs). When PBMCs were stimulated with phorbol myristate acetate/ionomycin or with anti-CD3/anti-CD28, the accumulation of LTalpha both at mRNA and protein levels was markedly inhibited by CsA. This inhibition is likely due to CsA's effect on the nuclear factor of activated T cell (NFAT) proteins binding to a novel NFAT-binding element at position -490 relative to LTalpha transcription start. LTbeta showed a distinct expression pattern and was insensitive to CsA. Thus, in addition to its effects on the expression of other TNF family members, such as TNFalpha, CD40-L, and CD95-L, CsA can block expression of surface LT complex by selectively inhibiting the expression of the LTalpha subunit. We propose that LT dysfunction and its downstream effects may contribute to immunosuppressive effects of CsA.
authors.affiliation: Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow State University, Russia.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Kuprash
authors.forename: Veronica E
authors.initials: VE
authors.lastname: Boitchenko
authors.forename: Felix O
authors.initials: FO
authors.lastname: Yarovinsky
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Rice
authors.forename: Alfred
authors.initials: A
authors.lastname: Nordheim
authors.forename: Andreas
authors.initials: A
authors.lastname: Rühlmann
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000096:biosynthesis* / Q000276:immunology; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000276:immunology; D008969:Molecular Sequence Data
chemical_list: D007166:Immunosuppressive Agents; C505886:LTB protein, human; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D016572:Cyclosporine