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CD40L overexpression on T cells and monocytes from patients with systemic lupus erythematosus is resistant to calcineurin inhibition

S-NC Liossis

First Department of Propedeutic Medicine, Athens University Medical School, Laikon Hospital, Athens, Greece

A M Dimopoulos

Department of Therapeutics, Athens University Medical School, Alexandra Hospital, Athens, Greece

D V Charalambopoulos

First Department of Propedeutic Medicine, Athens University Medical School, Laikon Hospital, Athens, Greece

M Mavrikakis

Department of Therapeutics, Athens University Medical School, Alexandra Hospital, Athens, Greece

P P Sfikakis

First Department of Propedeutic Medicine, Athens University Medical School, Laikon Hospital, Athens, Greece; 3 Amaryllidos Str, 154 52, Athens, Greece psfikakis{at}med.uoa.gr

To explore the regulatory defects underlying the overexpression of CD40 ligand (CD40L, CD154) in human lupus we studied the effects of cyclosporin-A (CsA), which blocks Ca²⁺/calcineurin-dependent CD40L gene expression, on peripheral blood-derived T cells and monocytes. In contrast to control subjects, CsA failed to inhibit the prolonged CD40L expression observed in vitro on anti-CD3-activated lupus T cells. Resistance to CsA was not restricted to CD4⁺ or CD8⁺ T cell subsets and was disease activity-independent. Experiments assessing the effects of dexamethasone on CD40L expression, as well as of CsA on the early activation marker CD69 expression and on surface CD40L cleavage, confirmed the unique regulation of CD40L in lupus T cells. On the other hand, co-culture with anti-CD3-activated T cells caused surface CD40L expression on monocytes, which was not an Fc receptor-mediated event. Lupus monocytes clearly overexpressed CD40L comparing to healthy and disease-control monocytes, and, similarly to lupus T cells, displayed a prominent resistance to CsA inhibitory effects. These findings indicate that, besides Ca²⁺/calcineurin-dependent mechanisms, other pathways are involved in the dysregulation of CD40L in SLE immune cells, dissection of which may have important therapeutic implications.

Key Words: CD40 ligand • CsA • T cells • monocytes • SLE

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