PI3K-mediated negative feedback regulation of IL-12 production in DCs.
Although interleukin 12 (IL-12) production by dendritic cells (DCs) confers protection against harmful invasions by regulating both innate and adaptive immunity, its dysregulation may have detrimental effects on the host. We show here that phosphoinositide 3-kinase (PI3K) negatively regulates IL-12 synthesis by DCs. We found that numerous stimuli that induced IL-12 production concomitantly elicited PI3K activation in DCs, but both PI3K(-/-) and PI3K inhibitor#150;treated DCs showed increased IL-12 production. Accordingly, an enhanced T helper type 1 (T(H)1) response was observed upon Leishmania major infection in PI3K(-/-) mice. Our findings indicate that a negative feedback mechanism exists that regulates IL-12 production during DC activation and may help prevent the excessive T(H)1 polarization that causes undesirable immune responses.
Fukao
Taro
T
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Tanabe
Masanobu
M
Terauchi
Yasuo
Y
Ota
Takayuki
T
Matsuda
Satoshi
S
Asano
Tomoichiro
T
Kadowaki
Takashi
T
Takeuchi
Tsutomu
T
Koyasu
Shigeo
S
D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism*; D005246:Feedback; D005260:Female; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases
C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D018664:Interleukin-12; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases