Constraints for monocyte-derived dendritic cell functions under inflammatory conditions

Tünde Fekete, Attila Szabo, Luca Beltrame, Nancy Vivar, Andor Pivarcsi, Arpad Lanyi, Duccio Cavalieri, Eva Rajnavölgyi, Bence Rethi

Research output: Contribution to journalArticlepeer-review

Abstract

The activation of TLRs expressed by macrophages or DCs, in the long run, leads to persistently impaired functionality. TLR signals activate a wide range of negative feedback mechanisms; it is not known, however, which of these can lead to long-lasting tolerance for further stimulatory signals. In addition, it is not yet understood how the functionality of monocyte-derived DCs (MoDCs) is influenced in inflamed tissues by the continuous presence of stimulatory signals during their differentiation. Here we studied the role of a wide range of DC-inhibitory mechanisms in a simple and robust model of MoDC inactivation induced by early TLR signals during differentiation. We show that the activation-induced suppressor of cytokine signaling 1 (SOCS1), IL-10, STAT3, miR146a and CD150 (SLAM) molecules possessed short-term inhibitory effects on cytokine production but did not induce persistent DC inactivation. On the contrary, the LPS-induced IRAK-1 downregulation could alone lead to persistent MoDC inactivation. Studying cellular functions in line with the activation-induced negative feedback mechanisms, we show that early activation of developing MoDCs allowed only a transient cytokine production that was followed by the downregulation of effector functions and the preservation of a tissue-resident non-migratory phenotype.

Original languageEnglish
Pages (from-to)458-469
Number of pages12
JournalEuropean Journal of Immunology
Volume42
Issue number2
DOIs
Publication statusPublished - Feb 2012

Keywords

  • DC
  • Endotoxin tolerance
  • IRAK-1
  • TLR

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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