RESUMO
BAY 41-2272 increases guanosine 3', 5'-cyclic monophosphate (cGMP) levels by stimulating soluble guanylate cyclase (sGC). In this study, we evaluated the effect of BAY 41-2272 on human T lymphocyte functions. Pretreating T cells for 24â¯h with BAY 41-2272 at 3⯵M and 30⯵M, followed by activation with 90â¯nM phorbol myristate acetate (PMA), inhibited interferon-gamma (IFN-γ) production, with 3⯵M and 30⯵M BAY causing 16.5-fold and 12.1-fold inhibition, respectively, compared to PMA alone (pâ¯<â¯0.05, one-way ANOVA followed by Tukey's test). We also observed suppressive effects on the expression of CD69, with 30⯵M BAY causing 3.55-fold lower expression than PMA/ionomycin (pâ¯<â¯0.001 one-way ANOVA followed by Tukey's test), and T-bet, with 30⯵M BAY causing 1.47-fold lower expression than PMA/ionomycin (pâ¯<â¯0.05, one-way ANOVA test followed by Tukey's test). Additionally, T lymphocyte proliferation was reduced 2.13-fold and 4.3-fold, respectively, by 3⯵M BAY and 30⯵M BAY compared to PMA/ionomycin (pâ¯<â¯0.01, pâ¯<â¯0.001, one-way ANOVA followed by Tukey's test). BAY 41-2272 inhibits human T lymphocyte function and may be explored as an immunomodulatory drug in patients with autoimmune/inflammatory diseases and lymphoproliferative syndromes.
Assuntos
Pirazóis/farmacologia , Piridinas/farmacologia , Linfócitos T/efeitos dos fármacos , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Proliferação de Células/efeitos dos fármacos , Guanilato Ciclase/metabolismo , Humanos , Fatores Imunológicos/metabolismo , Interferon gama/metabolismo , Ionomicina/farmacologia , Lectinas Tipo C/metabolismo , Linfócitos T/metabolismo , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
In our previous study, we have found that 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-pyrimidin-4-ylamine (BAY 41-2272), a guanylate cyclase agonist, activates human monocytes and the THP-1 cell line to produce the superoxide anion, increasing in vitro microbicidal activity, suggesting that this drug can be used to modulate immune functioning in primary immunodeficiency patients. In the present work, we investigated the potential of the in vivo administration of BAY 41-2272 for the treatment of Candida albicans and Staphylococcus aureus infections introduced via intraperitoneal and subcutaneous inoculation. We found that intraperitoneal treatment with BAY 41-2272 markedly increased macrophage-dependent cell influx to the peritoneum in addition to macrophage functions, such as spreading, zymosan particle phagocytosis and nitric oxide and phorbol myristate acetate-stimulated hydrogen peroxide production. Treatment with BAY 41-2272 was highly effective in reducing the death rate due to intraperitoneal inoculation of C. albicans, but not S. aureus. However, we found that in vitro stimulation of peritoneal macrophages with BAY 41-2272 markedly increased microbicidal activities against both pathogens. Our results show that the prevention of death by the treatment of C. albicans-infected mice with BAY 41-2272 might occur primarily by the modulation of the host immune response through macrophage activation. .