Cyclosporin A blocks the expression of lymphotoxin α, but not lymphotoxin β, in human peripheral blood mononuclear cells

The 2 lymphotoxin subunits LTα (also called tumor necrosis factor β [TNF-β]) and LTβ belong to the family of TNF-related cytokines. They form either a soluble homotrimeric ligand (LTα₃) that binds to and signals through CD120a/b (TNFRp55 and TNFRp75), or a membrane- associated heterotrimeric ligand (LTα₁β₂) that binds to and signals through the LTβ receptor (LTβR). In mice, LTβR 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 LTα and LTβ in human peripheral blood mononuclear cells (PBMCs). When PBMCs were stimulated with phorbol myristate acetate/ lonomycin or with anti-CD3/anti-CD28, the accumulation of LTα 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 LTα transcription start. LTβ 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 TNFα, CD40-L, and CD95-L, CsA can block expression of surface LT complex by selectively inhibiting the expression of the LTα subunit. We propose that LT dysfunction and its downstream effects may contribute to immunosuppressive effects of CsA.