Inhibiting STAT5 by the BET Bromodomain Inhibitor JQ1 Disrupts Human Dendritic Cell Maturation

Autor(es)

Toniolo, Patricia A. ^{[1, 2, 3, 4]} ; Liu, Suhu ^{[2, 3, 4]} ; Yeh, Jennifer E. ^{[2, 3, 4]} ; Moraes-Vieira, Pedro M. ^{[2, 5]} ; Walker, Sarah R. ^{[2, 3, 4]} ; Vafaizadeh, Vida ^[6] ; Barbuto, Jose Alexandre M. ^[1] ; Frank, David A. ^{[2, 3, 4]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, BR-05508900 Sao Paulo - Brazil

^[2] Harvard Univ, Sch Med, Boston, MA 02215 - USA

^[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 - USA

^[4] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 - USA

^[5] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Dept Med, Boston, MA 02215 - USA

^[6] Georg Speyer Haus, Inst Biomed Res, D-60956 Frankfurt - Germany

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF IMMUNOLOGY; v. 194, n. 7, p. 3180-3190, APR 1 2015.
• Citações Web of Science: 25

Resumo

Maturation of dendritic cells (DCs) is required to induce T cell immunity, whereas immature DCs can induce immune tolerance. Although the transcription factor STAT5 is suggested to participate in DC maturation, its role in this process remains unclear. In this study, we investigated the effect of STAT5 inhibition on LPS-induced maturation of human monocyte-derived DCs (Mo-DCs). We inhibited STAT5 by treating Mo-DCs with JQ1, a selective inhibitor of BET epigenetic readers, which can suppress STAT5 function. We found that JQ1 inhibits LPS-induced STAT5 phosphorylation and nuclear accumulation, thereby attenuating its transcriptional activity in Mo-DCs. The diminished STAT5 activity results in impaired maturation of Mo-DCs, as indicated by defective upregulation of costimulatory molecules and CD83, as well as reduced secretion of IL-12p70. Expression of constitutively activated STAT5 in JQ1-treated Mo-DCs overcomes the effects of JQ1 and enhances the expression of CD86, CD83, and IL-12. The activation of STAT5 in Mo-DCs is mediated by GM-CSF produced following LPS stimulation. Activated STAT5 then leads to increased expression of both GM-CSF and GM-CSFR, triggering an autocrine loop that further enhances STAT5 signaling and enabling Mo-DCs to acquire a more mature phenotype. JQ1 decreases the ability of Mo-DCs to induce allogeneic CD4(+) and CD8(+) T cell proliferation and production of proinflammatory cytokines. Furthermore, JQ1 leads to a reduced generation of inflammatory CD8(+) T cells and decreased Th1 differentiation. Thus, JQ1 impairs LPS-induced Mo-DC maturation by inhibiting STAT5 activity, thereby generating cells that can only weakly stimulate an adaptive-immune response. Therefore, JQ1 could have beneficial effects in treating T cell-mediated inflammatory diseases. (AU)

• Processo FAPESP: 12/01623-9 - Pirimetamina na imunoterapia antitumoral: relação entre a inibição de STAT3 e a indução de células dendríticas inflamatórias
• Beneficiário: Patricia Argenta Toniolo
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 09/54599-5 - Células dendríticas: elementos integrados do sistema imune - enfoque aplicado
• Beneficiário: Jose Alexandre Marzagão Barbuto
• Modalidade de apoio: Auxílio à Pesquisa - Temático