title: Dendritic cell maturation occurs through the inhibition of GSK-3β.
abstract: Dendritic cell (DC) maturation results in changes in antigen processing and presentation, governing the fate of adaptive immunity. Understanding the intracellular signaling pathways governing DC maturation is therefore critical. In this study, we observed that the kinase, GSK-3β, is present in its active form in resting immature DCs isolated from the spleen and bone marrow of mice. Induction of DC maturation using GM-CSF, IL-4 and TNF-α resulted in GSK-3β inhibition, as reflected by increased phosphorylation of Serine 9 on the kinase, and concomitant stabilization of its substrate, β-catenin. Treatment of immature DCs with a GSK-3β inhibitor increased cell surface expression of CD80, CD86 and CD40 on DCs, enhancing their ability to present antigen and activating IL-2 secretion by T cells. GSK-3β inhibition also parallels dendritic cell maturation in vivo. Our results show that GSK-3β signaling controls DC maturation and suggest that this kinase could be manipulated to modulate adaptive immunity.
authors: Transplantation Unit, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States. aalessandrini@partners.org
authors: Alessandro
authors: A
authors: Alessandrini
authors: Stephanie
authors: S
authors: De Haseth
authors: Michael
authors: M
authors: Fray
authors: Masahiro
authors: M
authors: Miyajima
authors: Robert B
authors: RB
authors: Colvin
authors: Winfred W
authors: WW
authors: Williams
authors: A
authors: A
authors: Benedict Cosimi
authors: Gilles
authors: G
authors: Benichou
references: J Biol Chem. 2004 Dec 3;279(49):51075-81
references: 15466414
references: J Biol Chem. 1997 Mar 21;272(12):7713-9
references: 9065430
references: Physiol Rev. 2002 Jan;82(1):97-130
references: 11773610
references: Cell. 1992 Dec 24;71(7):1065-8
references: 1335362
references: J Immunol. 2003 Dec 15;171(12):6323-7
references: 14662827
references: Curr Biol. 1996 Dec 1;6(12):1664-8
references: 8994831
references: J Biol Chem. 2007 Sep 21;282(38):27587-97
references: 17660512
references: Science. 1997 Mar 28;275(5308):1930-4
references: 9072970
references: J Biol Chem. 1998 Aug 7;273(32):19929-32
references: 9685326
references: Blood. 2000 Aug 1;96(3):1039-46
references: 10910920
references: J Leukoc Biol. 2002 Jul;72(1):107-14
references: 12101269
references: Int Immunol. 2004 Dec;16(12):1701-9
references: 15477228
references: J Exp Med. 2002 Apr 1;195(7):953-8
references: 11927638
references: Genes Dev. 1996 Oct 15;10(20):2527-39
references: 8895655
references: Nature. 1995 Dec 21-28;378(6559):785-9
references: 8524413
references: J Immunol. 1996 Sep 15;157(6):2645-53
references: 8805669
references: J Exp Med. 2001 Jan 15;193(2):F5-9
references: 11208869
references: Transplantation. 2003 Feb 27;75(4):521-8
references: 12605121
references: Blood. 2007 Feb 15;109(4):1584-92
references: 17032918
references: J Biol Chem. 2006 Jul 7;281(27):18878-87
references: 16644731
references: Blood. 2006 Sep 1;108(5):1435-40
references: 16684955
references: Nature. 1995 Apr 13;374(6523):617-22
references: 7715701
references: J Biol Chem. 2004 Jul 9;279(28):29450-60
references: 15123631
references: Eur J Immunol. 1996 Jul;26(7):1621-7
references: 8766570
references: Nat Med. 1997 May;3(5):499-500
references: 9142114
references: Immunity. 2007 Oct;27(4):610-24
references: 17936032
references: Am J Transplant. 2005 Dec;5(12):2807-13
references: 16302992
references: Nat Immunol. 2007 Feb;8(2):191-7
references: 17136045
references: Curr Opin Immunol. 2005 Oct;17(5):560-4
references: 16084707
references: Eur J Immunol. 2000 Jul;30(7):1813-22
references: 10940870
references: J Biol Chem. 1998 May 22;273(21):13150-6
references: 9582355
references: Blood. 2005 Jul 1;106(1):103-9
references: 15769893
references: Immunology. 2007 Oct;122(2):189-98
references: 17490435
references: Biochem J. 1994 Nov 1;303 ( Pt 3):701-4
references: 7980435