title: The human antimicrobial peptide LL-37, but not the mouse ortholog, mCRAMP, can stimulate signaling by poly(I:C) through a FPRL1-dependent pathway.
abstract: LL-37 is an antimicrobial peptide produced by human cells that can down-regulate the lipopolysaccharide-induced innate immune responses and up-regulate double-stranded (ds) RNA-induced innate responses through Toll-like receptor 3 (TLR3). The murine LL-37 ortholog, mCRAMP, also inhibited lipopolysaccharide-induced responses, but unlike LL-37, it inhibited viral-induced responses in mouse cells. A fluorescence polarization assay showed that LL-37 was able to bind dsRNA better than mCRAMP. In the human lung epithelial cell line BEAS-2B, LL-37, but not mCRAMP, colocalized with TLR3, and the colocalization was increased in the presence of dsRNA. The presence of poly(I:C) increased the accumulation of LL-37 in Rab5 endosomes. Signaling by cells induced with both LL-37 and poly(I:C) was sensitive to inhibitors that affect clathrin-independent trafficking, whereas signaling by poly(I:C) alone was not, suggesting that the LL-37-poly(I:C) complex trafficked to signaling endosomes by a different mechanism than poly(I:C) alone. siRNA knockdown of known LL-37 receptors identified that FPRL1 was responsible for TLR3 signaling induced by LL-37-poly(I:C). These results show that LL-37 and mCRAMP have different activities in TLR3 signaling and that LL-37 can redirect trafficking of poly(I:C) to effect signaling by TLR3 in early endosomes in a mechanism that involves FPRL1.
authors: Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana 47405-7005.
authors: Divyendu
authors: D
authors: Singh
authors: Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana 47405-7005.
authors: Rongsu
authors: R
authors: Qi
authors: Janssen Pharmaceutical Companies of Johnson & Johnson, Radnor, Pennsylvania 19087.
authors: Jarrat L
authors: JL
authors: Jordan
authors: Janssen Pharmaceutical Companies of Johnson & Johnson, Radnor, Pennsylvania 19087.
authors: Lani
authors: L
authors: San Mateo
authors: Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana 47405-7005. Electronic address: ckao@indiana.edu.
authors: C Cheng
authors: CC
authors: Kao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000502:physiology*; D054804:Cathelicidins / Q000502:physiology*; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D011070:Poly I-C / Q000494:pharmacology*; D011485:Protein Binding; D021381:Protein Transport; D044042:Receptors, Formyl Peptide / Q000378:metabolism* / Q000502:physiology; D044067:Receptors, Lipoxin / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; C105101:FPR2 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D011070:Poly I-C
references: J Exp Med. 2009 Dec 21;206(13):2967-76
references: 19995959
references: FASEB J. 2007 Sep;21(11):2897-905
references: 17446260
references: PLoS One. 2011;6(10):e26632
references: 22039520
references: Mol Ther. 2010 Mar;18(3):561-9
references: 20010917
references: J Inflamm (Lond). 2005 Nov 29;2:16
references: 16316467
references: Sci Transl Med. 2011 Mar 9;3(73):73ra19
references: 21389263
references: J Biol Chem. 2010 Nov 19;285(47):36635-44
references: 20855885
references: Mol Cancer Res. 2009 Jun;7(6):907-15
references: 19491199
references: Curr Opin Immunol. 2008 Aug;20(4):401-7
references: 18611439
references: Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8856-61
references: 10922046
references: FASEB J. 2008 Jan;22(1):159-67
references: 17709607
references: Oncogene. 2012 Jan 19;31(3):352-65
references: 21685939
references: Nature. 2007 Oct 4;449(7162):564-9
references: 17873860
references: EMBO J. 2006 Feb 22;25(4):683-92
references: 16467847
references: Cell Immunol. 2010;264(1):104-9
references: 20570250
references: FEMS Immunol Med Microbiol. 2009 Aug;56(3):233-40
references: 19527294
references: J Biol Chem. 2012 Sep 21;287(39):32617-29
references: 22865861
references: J Clin Invest. 1985 Oct;76(4):1427-35
references: 2997278
references: Nature. 2001 Oct 18;413(6857):732-8
references: 11607032
references: Int Immunol. 2006 Dec;18(12):1729-36
references: 17041145
references: Annu Rev Cell Biol. 1990;6:151-71
references: 2177341
references: J Biol Chem. 1993 Dec 5;268(34):25395-401
references: 8244972
references: Mol Pharmacol. 2013 Feb;83(2):389-98
references: 23160941
references: PLoS One. 2011;6(10):e25837
references: 22016778
references: Biochem Biophys Res Commun. 2004 Nov 5;324(1):382-6
references: 15465030
references: Biochim Biophys Acta. 2010 Dec;1798(12):2201-8
references: 20036634
references: Biochem J. 1999 Aug 1;341 ( Pt 3):501-13
references: 10417311
references: J Immunol. 2008 Oct 15;181(8):5522-9
references: 18832709
references: J Microsc. 2006 Dec;224(Pt 3):213-32
references: 17210054
references: Ann Rheum Dis. 2013 Jul;72(7):1239-48
references: 23172753
references: J Immunol. 2003 Dec 15;171(12):6690-6
references: 14662872
references: Mol Cell Biol. 2008 Jul;28(14):4507-19
references: 18490443
references: J Immunol. 2011 Dec 1;187(11):5653-9
references: 22048772
references: Nature. 2001 Nov 22;414(6862):454-7
references: 11719807