The Journal of Experimental Medicine
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Published online 24 November 2003 doi:10.1084/jem.20031701
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© Rockefeller University Press, 0022-1007/2003/12/1717 $5.00
The Journal of Experimental Medicine, Volume 198, Number 11, 1717-1727

IL-4–Stat6 Signaling Induces Tristetraprolin Expression and Inhibits TNF-{alpha} Production in Mast Cells

Kotaro Suzuki, Hiroshi Nakajima, Kei Ikeda, Yuko Maezawa, Akira Suto, Hiroaki Takatori, Yasushi Saito and Itsuo Iwamoto

Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan

Address correspondence to Hiroshi Nakajima, Dept. of Internal Medicine II, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba 260-8670, Japan. Phone: 81-43-226-2093; Fax: 81-43-226-2095; email: nakajimh{at}faculty.chiba-u.jp

Increasing evidence has revealed that mast cell–derived tumor necrosis factor {alpha} (TNF-{alpha}) plays a critical role in a number of inflammatory responses by recruiting inflammatory leukocytes. In this paper, we investigated the regulatory role of interleukin 4 (IL-4) in TNF-{alpha} production in mast cells. IL-4 inhibited immunoglobulin E–induced TNF-{alpha} production and neutrophil recruitment in the peritoneal cavity in wild-type mice but not in signal transducers and activators of transcription 6 (Stat6)–deficient mice. IL-4 also inhibited TNF-{alpha} production in cultured mast cells by a Stat6-dependent mechanism. IL-4–Stat6 signaling induced TNF-{alpha} mRNA destabilization in an AU-rich element (ARE)–dependent manner, but did not affect TNF-{alpha} promoter activity. Furthermore, IL-4 induced the expression of tristetraprolin (TTP), an RNA-binding protein that promotes decay of ARE-containing mRNA, in mast cells by a Stat6-dependent mechanism, and the depletion of TTP expression by RNA interference prevented IL-4–induced down-regulation of TNF-{alpha} production in mast cells. These results suggest that IL-4–Stat6 signaling induces TTP expression and, thus, destabilizes TNF-{alpha} mRNA in an ARE-dependent manner.

Key Words: mast cell–derived TNF-{alpha} • mRNA destabilization • RNA interference • AU-rich element • IgE

Abbreviations used in this paper: ARE, AU-rich element; DOX, doxycycline; GFP, green fluorescent protein; HSA, human serum albumin; MAP, mitogen-activated protein; RNAi, RNA interference; shRNA, short hairpin RNA; Stat6, signal transducers and activators of transcription 6; TTP, tristetraprolin.


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