ANTI-PROLIFERATIVE EFFECT OF NON STEROIDAL GLUCOCORTICOID RECEPTOR AGONIST COMPOUND A IN CELLS STIMULATED WITH SEG.

FERNÁNDEZ LYNCH, MJ; SARRATEA, MB; MALCHIODI, EL; DÍAZ, M; ANTONOGLOU, MB; FERNÁNDEZ, MM; NOLI TRUANT, S; DE MARZI, MC

Mar del Plata

Congreso; SAIC.SAI.SAFE.2016; 2016

ANTI-PROLIFERATIVE EFFECT OF NON STEROIDAL GLUCOCORTICOID RECEPTOR AGONIST COMPOUND A IN CELLS STIMULATED WITH SEG.Authors: Fernández Lynch, MJ1; Díaz, M1; Noli Truant, S1; Sarratea, MB1; Antonoglou, MB1; de Marzi, MC2; Malchiodi, EL1; Fernández, MM1. (1) Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Inmunología-IDEHU (UBA-CONICET), Buenos Aires, Argentina(2) Universidad Nacional de Lujan, INEDES, Lujan, Buenos Aires, Argentina.Keywords:S. aureus, SEGRAs, glucocorticoids, superantigens.Bacterial superantigens, such as SEG, are exotoxins thattriggerpeptide-non-specific T cell proliferation and proinflammatory cytokine release.Immunosuppressants, like glucocorticoids, are used to revert inflammatory actions in superantigen related diseases. However, we have previously reported resistance to dexamethasone by enterotoxin gene cluster and group II toxins in peripheral blood mononuclear cells (PBMCs).Non-steroidal glucocorticoid receptor agonists (SEGRAs), like Compound A, exert their action by transrepressing activation of proinflammatory pathways[Bossher 2005]. Therefore, we studied the pathways involved in glucocorticoid resistance and whether SEGRAs can exert a better immunosuppressive action than dexamethasone.SEG was recombinantly produced in E. coliand purified by Ni-NTA. PBMCs were enriched from heparinized blood using Ficoll-Hypaque gradient, cultured for 48 h for proliferation assessment with 3H-thymidine underdifferent stimuli (SEG 10 µg/ml, dexamethasone 10-5 M, Compound A 10-6 to 10-4M, rapamycin 1-200 nM and BAY 11-7082 1-50 µM.) The effect of SEG on macrophage cell line RAW and T cell line LBR was also assessed by proliferation assays.PBMCs proliferation induced by 10 µg/ml SEG is inhibited by NFκB inhibitor BAY 11-7082 at 10 µM (two way ANOVA p>0.05) showing the importance of this inflammatory transcription factor in the superantigen action mechanism.Ten µMcompound A also inhibits SEG-induced proliferation showing a better immunosuppressive activity than 10 µM dexamethasone treated cells which show significant proliferation (p0.05). The study on isolated cell lines shows that SEG is unable to induce proliferation lacking costimulatory signals rendering these pathways an interesting target.Understanding the underlying mechanisms of glucocorticoid resistance in staphylococcal toxin related diseases can help improve treatment outcome in patients, being SEGRAs promising drugs for treating these diseases.