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Autocrine Regulation of IL-21 Production in Human T Lymphocytes¹

Flavio Caprioli^*, Massimiliano Sarra^*, Roberta Caruso^*, Carmine Stolfi^*, Daniele Fina^*, Giuseppe Sica, Thomas T. MacDonald, Francesco Pallone^* and Giovanni Monteleone^2,*

^* Department of Internal Medicine and Department of Surgery, University Tor Vergata, Rome, Italy; and Institute of Cell and Molecular Science, Bart’s, and the London School of Medicine and Dentistry, London, United Kingdom

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 -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 -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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Eli and Edythe L. Broad Foundation, the Fondazione "Umber Di Mario," Rome, Giuliani SpA, Milan, Italy, and by a grant from Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy.

² Address correspondence and reprint requests to Dr. Giovanni Monteleone, Dipartimento di Medicina Interna, Università Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy. E-mail address: Gi.Monteleone{at}Med.uniroma2.it

³ Abbreviations used in this paper: siRNA, small interfering RNA; LPL, lamina propria lymphocyte; GAS, IFN- activated site; AV, annexin V; PI, propidium iodide.