Toll-like receptor agonists partially restore the production of pro-inflammatory cytokines and type I interferon in Sézary syndrome

• Published in: Oncotarget Vol. 7; no. 46; pp. 74592 - 74601
• Main Authors: Manfrere, Kelly C G, Torrealba, Marina P, Miyashiro, Denis R, Oliveira, Luanda M S, de Carvalho, Gabriel C, Lima, Josenilson F, Branco, Anna Claudia C C, Pereira, Nátalli Z, Pereira, Juliana, Sanches, Jr, José A, Sato, Maria N
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 15.11.2016
• Subjects: Aged; Cytokines - blood; Cytokines - metabolism; Female; Humans; Immunity, Innate; Inflammation Mediators - blood; Inflammation Mediators - metabolism; Interferon Type I - blood; Interferon Type I - metabolism; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Male; Middle Aged; Research Paper: Immunology; Sezary Syndrome - blood; Sezary Syndrome - immunology; Sezary Syndrome - metabolism; Toll-Like Receptors - agonists; type I interferon; Immune response; innate immunity; Toll-like receptor agonists; Immunology and Microbiology Section; cytokines; Sézary syndrome; Immunity
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.12816

Sézary syndrome (SS) carries a poor prognosis, and infections represent the most frequent cause of death in SS patients. Toll-like receptors (TLRs) are a family of innate immune receptors that induce protective immune responses against infections. We sought to evaluate the ability of TLR agonists to induce inflammatory cytokine, Th2 cytokine, and type I interferon (IFN-I) production by peripheral blood mononuclear cells (PBMC) of untreated SS patients. We detected impaired IL-6, IL-10 and IL-13 secretion by PBMC induced by the agonists for TLR5, TLR3, TLR7 and TLR9 in SS patients, while it was partially recovered by TLR2/TLR4 and TLR7/8 agonists TNF secretion was restored following stimulation with TLR2/TLR4 agonists. IFN-γ was scarcely produced upon TLR activation in SS cells, albeit TLR 7/8 (CL097) enhanced their secretion at lower levels than the control group. TLR9 agonist efficiently induced IFN-I in SS patients, although this positive regulation was not observed for other cytokines, in direct contrast to the broad activity of CL097. Among the TLR agonists, TLR4 was able to induce pro-inflammatory, IL-10 and Th2 secretion, while TLR7-8 agonist induced the inflammatory cytokines, IFN-I and IFN-γ. These findings reveal a dysfunctional cytokine response upon both extracellular and intracellular TLR activation in SS patients, which was partially restored by TLRs agonists.