Dual requirement for STAT signaling in dendritic cell immunobiology

Gloria Donninelli, Isabella Sanseverino, Cristina Purificato, Sandra Gessani, Maria Cristina Gauzzi

Research output: Contribution to journalArticle

Abstract

Dendritic cells (DC) represent an attractive target for therapeutic manipulation of the immune system and enhancement of insufficient immune response in cancer. STAT family members play key roles in the differentiation and activation of DC, a feature that is currently being exploited in DC-based therapies. We previously reported that the small-molecule Stattic, originally developed as a STAT3-specific inhibitor, also inhibits STAT1 and STAT2 phosphorylation in DC exposed to cytokines or LPS. Aim of this study was to investigate the functional consequences of in vitro treatment with Stattic on DC immunobiology. Interestingly, we observed an opposite effect of Stattic on DC immunophenotype depending on the activation state. While the expression of costimulatory, coinhibitory, MHC class II and CD83 molecules was enhanced in immature DC exposed to Stattic, the LPS induced up-modulation of these molecules was strongly repressed. An effective blockade of LPS-induced secretion of proinflammatory cytokines and capacity to stimulate a Th1 polarization was also observed in the presence of Stattic. Our results indicate that the immunological consequences of STAT inhibition in DC vary depending on the cell activation state. This knowledge is of relevance for anticipating potential effects of STAT-targeted therapeutics, and pursuing selective DC manipulation in clinical applications.

Original languageEnglish
Pages (from-to)342-347
Number of pages6
JournalImmunobiology
Volume223
Issue number3
DOIs
Publication statusPublished - Mar 2018

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Dendritic Cells
Cytokines
Cell- and Tissue-Based Therapy
Immune System
Therapeutics
Phosphorylation
stattic

Keywords

  • Anti-Inflammatory Agents/pharmacology
  • Antigens, CD/metabolism
  • Cell Differentiation/drug effects
  • Cells, Cultured
  • Cyclic S-Oxides/pharmacology
  • Cytokines/metabolism
  • Dendritic Cells/immunology
  • Humans
  • Immunoglobulins/metabolism
  • Immunophenotyping
  • Lipopolysaccharides/immunology
  • Lymphocyte Activation
  • Membrane Glycoproteins/metabolism
  • Neoplasms/drug therapy
  • Phosphorylation
  • STAT3 Transcription Factor/antagonists & inhibitors
  • Signal Transduction
  • Small Molecule Libraries
  • T-Lymphocytes/immunology

Cite this

Dual requirement for STAT signaling in dendritic cell immunobiology. / Donninelli, Gloria; Sanseverino, Isabella; Purificato, Cristina; Gessani, Sandra; Gauzzi, Maria Cristina.

In: Immunobiology, Vol. 223, No. 3, 03.2018, p. 342-347.

Research output: Contribution to journalArticle

Donninelli, Gloria ; Sanseverino, Isabella ; Purificato, Cristina ; Gessani, Sandra ; Gauzzi, Maria Cristina. / Dual requirement for STAT signaling in dendritic cell immunobiology. In: Immunobiology. 2018 ; Vol. 223, No. 3. pp. 342-347.
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AB - Dendritic cells (DC) represent an attractive target for therapeutic manipulation of the immune system and enhancement of insufficient immune response in cancer. STAT family members play key roles in the differentiation and activation of DC, a feature that is currently being exploited in DC-based therapies. We previously reported that the small-molecule Stattic, originally developed as a STAT3-specific inhibitor, also inhibits STAT1 and STAT2 phosphorylation in DC exposed to cytokines or LPS. Aim of this study was to investigate the functional consequences of in vitro treatment with Stattic on DC immunobiology. Interestingly, we observed an opposite effect of Stattic on DC immunophenotype depending on the activation state. While the expression of costimulatory, coinhibitory, MHC class II and CD83 molecules was enhanced in immature DC exposed to Stattic, the LPS induced up-modulation of these molecules was strongly repressed. An effective blockade of LPS-induced secretion of proinflammatory cytokines and capacity to stimulate a Th1 polarization was also observed in the presence of Stattic. Our results indicate that the immunological consequences of STAT inhibition in DC vary depending on the cell activation state. This knowledge is of relevance for anticipating potential effects of STAT-targeted therapeutics, and pursuing selective DC manipulation in clinical applications.

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