Interleukin-10-induced gene expression and suppressive function are selectively modulated by the PI3K-Akt-GSK3 pathway.
Interleukin-10 (IL-10) is an immunosuppressive cytokine that inhibits inflammatory gene expression. Phosphatidylinositol 3-kinase (PI3K) -mediated signalling regulates inflammatory responses and can induce IL-10 production, but a role for PI3K signalling in cellular responses to IL-10 is not known. In this study we investigated the involvement of the PI3K-Akt-GSK3 signalling pathway in IL-10-induced gene expression and IL-10-mediated suppression of Toll-like receptor-induced gene expression in primary human macrophages. A combination of loss and gain of function approaches using kinase inhibitors, expression of constitutively active Akt, and RNA interference in primary human macrophages showed that expression of a subset of IL-10-inducible genes was dependent on PI3K-Akt signalling. The effects of PI3K-Akt signalling on IL-10 responses were mediated at least in part by glycogen synthase kinase 3 (GSK3). In accordance with a functional role for PI3K pathways in contributing to the suppressive actions of IL-10, PI3K signalling augmented IL-10-mediated inhibition of lipopolysaccharide-induced IL-1, IL-8 and cyclo-oxygenase-2 expression. The PI3K signalling selectively modulated IL-10 responses, as it was not required for inhibition of tumour necrosis factor expression or for induction of certain IL-10-inducible genes such as SOCS3. These findings identify a new mechanism by which PI3K-mediated signalling can suppress inflammation by regulating IL-10-mediated gene induction and anti-inflammatory function.
Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery, New York, NY 10021, USA.
Taras T
TT
Antoniv
Lionel B
LB
Ivashkiv
D000730:Androstadienes / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D016753:Interleukin-10 / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D038362:Glycogen Synthase Kinase 3; D016753:Interleukin-10; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C448021:glycogen synthase kinase 3 alpha
J Biol Chem. 2008 Aug 8;283(32):21934-44
18550525
Immunity. 2006 May;24(5):563-74
16713974
Immunity. 1999 Jan;10(1):39-49
10023769
Cytokine. 2003 Oct;24(1-2):46-56
14561490
Nat Immunol. 2008 Apr;9(4):378-87
18345002
Trends Immunol. 2003 Jul;24(7):358-63
12860525
Annu Rev Immunol. 2001;19:683-765
11244051
Trends Immunol. 2010 Jan;31(1):24-31
19836308
Trends Cell Biol. 2004 Nov;14(11):628-38
15519852
Nat Immunol. 2008 Feb;9(2):186-93
18084294
J Immunol. 2002 Sep 1;169(5):2253-63
12193690
Nat Rev Immunol. 2005 Dec;5(12):953-64
16322748
Immunol Rev. 2008 Dec;226:205-18
19161426
J Clin Invest. 2007 May;117(5):1155-66
17476345
J Immunol. 2009 Jul 15;183(2):856-64
19542364
J Immunol. 2007 Dec 1;179(11):7215-9
18025162
J Immunol. 2003 Nov 15;171(10):5034-41
14607900
Immunobiology. 2005;210(2-4):87-95
16164015
J Biol Chem. 1997 Dec 12;272(50):31515-24
9395488
Immunity. 2008 Oct 17;29(4):565-77
18848473
J Biol Chem. 2009 Apr 10;284(15):9643-7
19064989
J Immunol. 2007 Mar 1;178(5):2623-9
17312100
Cell. 2007 Jun 29;129(7):1261-74
17604717
Nat Immunol. 2005 Aug;6(8):751-2
16034428
Immunity. 2005 Oct;23(4):361-74
16226502
Arthritis Rheum. 2006 Sep;54(9):2711-21
16947381
Blood. 2008 Aug 1;112(3):635-43
18492954
J Biol Chem. 1996 Jul 5;271(27):16357-62
8663063
Nat Immunol. 2005 Aug;6(8):777-84
16007092
J Immunol. 2004 Jan 1;172(1):567-76
14688368
Cytokine. 2000 Jul;12(7):934-43
10880238
Annu Rev Immunol. 2004;22:563-98
15032589