IL-4-Stat6 signaling induces tristetraprolin expression and inhibits TNF-alpha production in mast cells.
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.
Suzuki
Kotaro
K
Department of Internal Medicine II, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba 260-8670, Japan.
Nakajima
Hiroshi
H
Ikeda
Kei
K
Maezawa
Yuko
Y
Suto
Akira
A
Takatori
Hiroaki
H
Saito
Yasushi
Y
Iwamoto
Itsuo
I
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D017874:Immediate-Early Proteins / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D017931:DNA Primers; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse; D015847:Interleukin-4