Autocrine regulation of IL-21 production in human T lymphocytes.
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
Flavio
F
Department of Internal Medicine, University Tor Vergata, Via Montpellier 1, Rome, Italy.
Sarra
Massimiliano
M
Caruso
Roberta
R
Stolfi
Carmine
C
Fina
Daniele
D
Sica
Giuseppe
G
MacDonald
Thomas T
TT
Pallone
Francesco
F
Monteleone
Giovanni
G
D019898:Autocrine Communication; D017252:CD3 Complex / Q000032:analysis; D002478:Cells, Cultured; D003424:Crohn Disease / Q000276:immunology; D016207:Cytokines / Q000494:pharmacology; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007422:Intestines / Q000276:immunology; D009092:Mucous Membrane / Q000276:immunology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D000098546:Interleukin-21
D017252:CD3 Complex; D016207:Cytokines; D007378:Interleukins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000098546:Interleukin-21