Il-19 reduces VSMC activation by regulation of mRNA regulatory factor HuR and reduction of mRNA stability.
While much is known about the deleterious effects of pro-inflammatory cytokines on development of vascular disease, little is reported on the direct effects of anti-inflammatory cytokines on the vascular smooth muscle cell (VSMC) response to injury. Interleukin-19 (IL-19) is a recently described Th2, anti-inflammatory interleukin. We have previously reported that IL-19 is absent in normal VSMC, but induced in VSMC by inflammatory cytokines and in arteries by injury. IL-19 is anti-proliferative for VSMC. The purpose of this study is to determine the molecular mechanism of these effects. In cultured, primary human VSMC, IL-19 reduces abundance of proliferative and inflammatory gene proteins and mRNA, including Cyclin D1, IL-1beta, IL-8, and COX2. IL-19 does not inhibit NF-kappaB, but does transiently reduce cytoplasmic abundance of the mRNA stability factor HuR. The mRNA stabilizing function of HuR is linked to its phosphorylation and cytoplasmic translocation. IL-19 reduces serine phosphorylation of HuR, and activation of PKCalpha, a known regulator of HuR translocation. Actinomycin D transcription blockade demonstrates that IL-19 treatment significantly reduces stability of proliferative and inflammatory mRNAs. Knock down of HuR with siRNA also reduces stability of these inflammatory mRNA transcripts. These data indicate that IL-19 has direct effects on VSMC mRNA stability. One potential mechanism whereby IL-19 reduces the VSMC response to injury is by regulation of HuR abundance and cytoplasmic translocation, with a subsequent decrease in mRNA half-life of proliferative and inflammatory mRNA transcripts.
Cuneo
Anthony A
AA
Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Herrick
David
D
Autieri
Michael V
MV
D000954:Antigens, Surface / Q000235:genetics* / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D006801:Humans; D007378:Interleukins / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism*; D020871:RNA Stability / Q000187:drug effects; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D007378:Interleukins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins
Int Immunopharmacol. 2004 May;4(5):615-26
15120647
J Lipid Res. 2005 Jun;46(6):1081-92
15834121
Annu Rev Immunol. 2004;22:929-79
15032600
J Biol Chem. 1996 Aug 16;271(33):20108-12
8702732
Arterioscler Thromb Vasc Biol. 1999 Dec;19(12):2847-53
10591660
Bioessays. 2004 Jun;26(6):646-55
15170862
Am J Physiol Heart Circ Physiol. 2004 Aug;287(2):H866-71
15072956
J Cell Physiol. 2008 Nov;217(2):558-68
18615582
Nucleic Acids Res. 2006 Jan 03;33(22):7138-50
16391004
Mol Biol Cell. 2007 Jun;18(6):2137-48
17392515
Cardiovasc Res. 2008 Aug 1;79(3):360-76
18487233
FASEB J. 2006 Oct;20(12):2112-4
16935932
Pharmacol Rev. 2003 Mar;55(1):133-66
12615956
EMBO J. 1998 Jun 15;17(12):3448-60
9628880
J Immunol. 2009 Jan 15;182(2):802-10
19124723
Am J Pathol. 2008 Sep;173(3):901-9
18669613
Nucleic Acids Res. 2001 Jan 1;29(1):246-54
11125104
Cell Signal. 2008 Dec;20(12):2165-73
18585896
Mol Cell Biol. 1996 Apr;16(4):1490-9
8657122
Genes Immun. 2000 Oct;1(7):442-50
11196675
Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12065-70
16099831
J Clin Invest. 1997 Nov 15;100(10):2443-8
9366558
Nature. 1993 Apr 29;362(6423):801-9
8479518
Circ Res. 2001 May 11;88(9):877-87
11348996
Mol Cell. 2005 Sep 16;19(6):777-89
16168373
J Biol Chem. 2005 Jun 17;280(24):22819-26
15824116