Oncotarget

Research Papers: Immunology:

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

Kelly C. G. Manfrere, Marina P. Torrealba, Denis R. Miyashiro, Luanda M. S. Oliveira, Gabriel C. de Carvalho, Josenilson F. Lima, Anna Claudia C. C. Branco, Nátalli Z. Pereira, Juliana Pereira, José A. Sanches, Jr and Maria N. Sato _

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Oncotarget. 2016; 7:74592-74601. https://doi.org/10.18632/oncotarget.12816

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Abstract

Kelly C. G. Manfrere1, Marina P. Torrealba1, Denis R. Miyashiro2, Luanda M. S. Oliveira1, Gabriel C. de Carvalho1, Josenilson F. Lima1, Anna Claudia C. C. Branco1, Nátalli Z. Pereira1, Juliana Pereira3, José A. Sanches, Jr2,* and Maria N. Sato1,*

1 Department of Dermatology, Laboratory of Medical Investigation, LIM 56, Tropical Medicine Institute of São Paulo, University of São Paulo Medical School, Brazil

2 Department of Dermatology, Cutaneous Lymphoma Clinic, Hospital das Clínicas, University of São Paulo, Medical School, Brazil

3 Department of Hematology, University of São Paulo Medical School, Brazil

* These authors share the mentorship, critical revision and supervision of this study

Correspondence to:

Maria N. Sato, email:

Keywords: Sé,zary syndrome, innate immunity, Toll-like receptor agonists, cytokines, type I interferon, Immunology and Microbiology Section, Immune response, Immunity

Received: July 28, 2016 Accepted: October 14, 2016 Published: October 21, 2016

Abstract

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.


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