DEXAMETHASONE COUNTERACTS THE IMMUNOSTIMULATORY EFFECTS OF TRIIODOTHYRONINE (T3) ON DENDRITIC CELLS”

MARÍA M. MONTESINOS; VANINA A. ALAMINO; IVÁN D. MASCANFRONI, ; SEBASTIÁN SUSPERREGUY; NICOLÁS GIGENA; ANA M. MASINI-REPISO; GABRIEL A. RABINOVICH; CLAUDIA G. PELLIZAS

STEROIDS

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2012 vol. 77 p. 67 - 76

0039-128X

Glucocorticoids (GCs) are widely used as anti-inflammatory and immunosuppressive agents. Severalstudies have indicated the important role of dendritic cells (DCs), highly specialized antigen-presentingand immunomodulatory cells, in GC-mediated suppression of adaptive immune responses. Recently, wedemonstrated that triiodothyronine (T3) has potent immunostimulatory effects on bone marrow-derivedmouse DCs through a mechanism involving T3 binding to cytosolic thyroid hormone receptor (TR) b1,rapid and sustained Akt activation and IL-12 production. Here we explored the impact of GCs on T3-mediatedDC maturation and function and the intracellular events underlying these effects. Dexamethasone(Dex), a synthetic GC, potently inhibited T3-induced stimulation of DCs by preventing the augmentedexpression of maturation markers and the enhanced IL-12 secretion through mechanisms involvingthe GC receptor. These effects were accompanied by increased IL-10 levels following exposure of T3-conditionedDCs to Dex. Accordingly, Dex inhibited the immunostimulatory capacity of T3-matured DCs onnaive T-cell proliferation and IFN-c production while increased IL-10 synthesis by allogeneic T cell cultures.A mechanistic analysis revealed the ability of Dex to dampen T3 responses through modulationof Akt phosphorylation and cytoplasmic-nuclear shuttling of nuclear factor-jB (NF-jB). In addition,Dex decreased TRb1 expression in both immature and T3-maturated DCs through mechanisms involvingthe GC receptor. Thus GCs, which are increased during the resolution of inflammatory responses, counteractthe immunostimulatory effects of T3 on DCs and their ability to polarize adaptive immuneresponses toward a T helper (Th)-1-type through mechanisms involving, at least in part, NF-jB- andTRb1-dependent pathways. Our data provide an alternative mechanism for the anti-inflammatory effectsof GCs with critical implications in immunopathology at the cross-roads of the immune-endocrinecircuits.