INVESTIGADORES
SUSPERREGUY Sebastian
congresos y reuniones científicas
Título:
New insights into Glucocorticoid effect on T3 action in mice dendritic cells
Autor/es:
MONTESINOS MM; ALAMINO VA;; MASCANFRONI ID;; SUSPERREGUY S; ; MASINI-REPISO AM; ; RABINOVICH GA; ; PELLIZAS CG
Reunión:
Congreso; 14th International Thyroid Congress; 2010
Resumen:
Abstract:
Glucocorticoids (GC) are widely used as antiinflammatory and
immunosuppressive agents in the therapy ofmany autoimmune and allergic
diseases and in transplantation to prevent rejection. Several studies
have indicated theimportant role of antigen-presenting cells(APC) in
GC-mediated suppression of immunity. Among APC, dendritic cells(DC) are
considered to be the most efficient and indispensable to stimulate naïve
T cells and induce antigen-specificimmune responses (Guermonprez et
al., 2002). Given the remarkable plasticity of these cells, manipulation
of theirfunction to favor the induction of DC with immunogenic or
tolerogenic properties could be exploited in order to stimulateor
attenuate immune responses (Steinman & Banchereau, 2007). Mice DC
are generated from bone marrow (immatureDC:iDC) and the exposure to
pro-inflammatory stimuli (lipopolysaccharide,LPS) generates mature DC
(mDC) thatstimulate T cells. We have provided evidence for thyroid
hormone receptor (TR) b1 expression and triiodothyronine (T3)stimulatory
action on DC (Mascanfroniet al, FASEB Journal, 2008) by a mechanism
involving T3 binding to cytosolicTRb1 and a rapid and sustained Akt
activation dependent on TRb1 and essential for supporting T3-induced
DCmaturation and IL-12 production (Mascanfroni et al., J BiolChem,
2010). Recently, we demonstrated that Dexamethasone(Dex: synthetic GC)
reduced TRb1 expression in DC by a mechanism that involved the
glucocorticoid receptor (GR) (Montesinos et al., Arquivos Brasileiros de
Endocrinologia & Metabologia, 2009). The aim of this study was to
furtherevaluate the effect of Dex on T3 action in DC and to analyze the
signalling pathway involved. Mice DC were cultured frombone marrow with
GM-CSF for 7 days. Afterwards, iDC were pulsed with Dex 10 nM, LPS 100
ng/ml (positive control) orT3 5 nM for 18 h. After cell harvesting, DC
surface phenotype was determined by flow cytometry and cytokine
productionby ELISA. The ability of treated-DC to stimulate T cells was
assessed in a mixed lymphocyte reaction (MLR). Wemeasured
Akt-phosphorylation by Western Blot. Results: 1) the increment in
DCmaturation markers and IL-12-producingDC induced by T3 and LPS was
abolished by Dex by a mechanism that involved GR (it was prevented by a
GRantagonist: RU486). Besides, Dex increase IL-10 levels in DC maturated
with T3 and LPS. 2) Dex abolished T3-effectinducing DC able to
stimulate IL-10 and toinhibit INFg production by T cells in a MLR. 3)
T3-induced Akt phosphorylationwas inhibited by Dex. These results
indicate that GC are able to act through GR on LPS and T3-activated DC
byinhibiting production of the pro-inflammatory response by these cells.
Moreover, GC prevent T cell activation induced byT3. As the present
work demonstrates that Dex prevented Akt activation induced by T3 by a
mechanism that mayinvolvethe downregulation of TRβ1 induced by Dex, the
findings achieved are of physiologic and therapeutic relevance asAkt
activation has been shown to be of critical importance for promoting DC
survival which is an essential requirement inDC-based tumor vaccines
(Park et al., 2006). Hence, the use of GC in antitumor therapy should be
reconsidered, mainlyin specific protocols involving DC directed to
tumor antigen.