IL-21 has pathologic function in immune-inflammatory diseases. IL-21 mediates its functions through a heterodimeric receptor, composed of a specific subunit, termed IL-21R, and the common gamma-chain. IL-21 is mostly produced by CD4(+) T cells, but molecular mechanisms that regulate IL-21 synthesis are not fully understood. The fact that CD4(+) T cells express high levels of IL-21R and are capable of functionally responding to IL-21 raises the possibility that IL-21 may regulate its own production. We here show that IL-21 enhances IL-21 RNA and protein expression in human peripheral blood CD3(+) T cells in a dose- and time-dependent fashion. Additionally, both IL-7 and IL-15, but not IL-4, induce IL-21, thus suggesting that common gamma-chain signals are not sufficient to promote IL-21 synthesis. Analysis of molecular mechanisms underlying IL-21 induction reveals that IL-21 activates Stat3 and enhances its recruitment to IL-21 gene promoter. Pharmacologic inhibition and knockdown of Stat3 by small interference RNA largely prevent IL-21 induction in IL-21-treated cells. Consistently, IL-21 is inducible in T cells by IL-6, another cytokine that activates Stat3. Finally, we show that IL-21 positively regulates its own expression in human intestinal CD3(+) lamina propria lymphocytes, and blockade of endogenous IL-21 in cultures of CD3(+) lamina propria lymphocytes isolated from patients with Crohn's disease, a chronic inflammatory bowel disease characterized by high IL-21, down-regulates Stat3 activation and IL-21 expression. These data suggest the existence of a positive autocrine loop that could help to amplify and stabilize IL-21-driven, T cell-mediated responses.

Caprioli, F., Sarra, M., Caruso, R., Stolfi, C., Fina, D., Sica, G., et al. (2008). Autocrine regulation of IL-21 production in human T lymphocytes. JOURNAL OF IMMUNOLOGY, 180(3), 1800-1807.

Autocrine regulation of IL-21 production in human T lymphocytes

Stolfi, C;SICA, GIUSEPPE;PALLONE, FRANCESCO;MONTELEONE, GIOVANNI
2008-02-01

Abstract

IL-21 has pathologic function in immune-inflammatory diseases. IL-21 mediates its functions through a heterodimeric receptor, composed of a specific subunit, termed IL-21R, and the common gamma-chain. IL-21 is mostly produced by CD4(+) T cells, but molecular mechanisms that regulate IL-21 synthesis are not fully understood. The fact that CD4(+) T cells express high levels of IL-21R and are capable of functionally responding to IL-21 raises the possibility that IL-21 may regulate its own production. We here show that IL-21 enhances IL-21 RNA and protein expression in human peripheral blood CD3(+) T cells in a dose- and time-dependent fashion. Additionally, both IL-7 and IL-15, but not IL-4, induce IL-21, thus suggesting that common gamma-chain signals are not sufficient to promote IL-21 synthesis. Analysis of molecular mechanisms underlying IL-21 induction reveals that IL-21 activates Stat3 and enhances its recruitment to IL-21 gene promoter. Pharmacologic inhibition and knockdown of Stat3 by small interference RNA largely prevent IL-21 induction in IL-21-treated cells. Consistently, IL-21 is inducible in T cells by IL-6, another cytokine that activates Stat3. Finally, we show that IL-21 positively regulates its own expression in human intestinal CD3(+) lamina propria lymphocytes, and blockade of endogenous IL-21 in cultures of CD3(+) lamina propria lymphocytes isolated from patients with Crohn's disease, a chronic inflammatory bowel disease characterized by high IL-21, down-regulates Stat3 activation and IL-21 expression. These data suggest the existence of a positive autocrine loop that could help to amplify and stabilize IL-21-driven, T cell-mediated responses.
1-feb-2008
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/12 - GASTROENTEROLOGIA
English
Con Impact Factor ISI
Antigens, CD3; STAT3 Transcription Factor; Autocrine Communication; Cells, Cultured; Inflammatory Bowel Diseases; RNA Interference; Feedback, Physiological; Interleukins; Mucous Membrane; T-Lymphocytes; Humans; Gene Expression Regulation; Cytokines; Promoter Regions, Genetic; RNA, Small Interfering; Intestines; Crohn Disease
Caprioli, F., Sarra, M., Caruso, R., Stolfi, C., Fina, D., Sica, G., et al. (2008). Autocrine regulation of IL-21 production in human T lymphocytes. JOURNAL OF IMMUNOLOGY, 180(3), 1800-1807.
Caprioli, F; Sarra, M; Caruso, R; Stolfi, C; Fina, D; Sica, G; Macdonald, T; Pallone, F; Monteleone, G
Articolo su rivista
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/56914
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 101
  • ???jsp.display-item.citation.isi??? 91
social impact