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Blood, 1 September 2002, Vol. 100, No. 5, pp. 1721-1727
IMMUNOBIOLOGY
Cyclosporin A blocks the expression of lymphotoxin  , but not
lymphotoxin  , in human peripheral blood mononuclear
cells
Dmitry V. Kuprash,
Veronica
E. Boitchenko,
Felix O. Yarovinsky,
Nancy R. Rice,
Alfred Nordheim,
Andreas Rühlmann, and
Sergei A. Nedospasov
From the Laboratory of Molecular Immunology, Engelhardt
Institute of Molecular Biology, Russian Academy of Sciences, and
Belozersky Institute of Physico-Chemical Biology, Moscow State
University, Moscow, Russia; Department of Molecular Biology, Institute
for Cell Biology, Eberhard-Karls-University Tübingen,
Tübingen, Germany; Regulation of Cell Growth Laboratory, Division
of Basic Sciences, National Cancer Institute Frederick, and Intramural
Research Support Program, Science Applications International
Corporation (SAIC) Frederick and Laboratory of Molecular
Immunoregulation, Division of Basic Sciences, National Cancer Institute
Frederick, Frederick, MD.
The 2 lymphotoxin subunits LT (also called tumor necrosis factor
 [TNF-]) and LT belong to the family of TNF-related
cytokines. They form either a soluble homotrimeric ligand
(LT3) that binds to and signals through CD120a/b
(TNFRp55 and TNFRp75), or a membrane-associated heterotrimeric ligand
(LT12) that binds to and signals through the LT receptor (LTR). In mice, LTR 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 LT and
LT 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 LT 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 LT transcription start. LT 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 TNF,
CD40-L, and CD95-L, CsA can block expression of surface LT complex by selectively inhibiting the expression of the LT subunit. We propose that LT dysfunction and its downstream effects may contribute to
immunosuppressive effects of CsA.
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