Targeting TLR/IL-1R signalling in human diseases.
The members of Toll-like receptor/interleukin (IL)-1 receptor (TLR/IL-1R) superfamily play a fundamental role in the immune response. These receptors detect microbial components and trigger complex signalling pathways that result in increased expression of multiple inflammatory genes. On the other hand, an aberrant activation of TLR/IL-1R signalling can promote the onset of inflammatory and autoimmune diseases, raising the interest in the development of therapeutic strategies for the control of their function. In this review, we illustrate the structural and functional features of TLR/IL-1R proteins and discuss some recent advances in the approaches undertaken to develop anti-inflammatory therapeutic drugs. In particular, we will focus on inhibitors, such as decoy peptides and synthetic mimetics, that interfere with protein-protein interactions between signalling molecules of the TLR/IL-1R superfamily. Given their central role in innate and adaptive immune responses, it is foreseen that pharmaceutical modulation of TLR/IL-1R signalling pathways by these drugs might yield clinical benefits in the treatment of inflammatory and autoimmune diseases.
Loiarro
Maria
M
Department of Public Health and Cell Biology, University of Rome "Tor Vergata", 00133 Rome, Italy.
Ruggiero
Vito
V
Sette
Claudio
C
D000595:Amino Acid Sequence; D000818:Animals; D004194:Disease; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017472:Receptors, Interleukin-1 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
D053594:Myeloid Differentiation Factor 88; D010455:Peptides; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors
Nat Rev Drug Discov. 2006 Jul;5(7):549-63
16773072
Proc Natl Acad Sci U S A. 2009 Jun 23;106(25):10260-5
19506249
Curr Drug Discov Technol. 2008 Mar;5(1):29-38
18537565
J Natl Cancer Inst. 2006 May 3;98(9):574-5
16670380
Adv Exp Med Biol. 2009;653:48-57
19799111
Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7971-6
12799462
J Biol Chem. 2009 Oct 9;284(41):28093-28103
19679662
Cell Signal. 2007 Dec;19(12):2549-57
17905570
Curr Drug Targets. 2009 Nov;10(11):1139-55
19715534
J Intern Med. 2007 Jun;261(6):511-28
17547708
Immunol Cell Biol. 2007 Aug-Sep;85(6):490-4
17667933
Science. 2003 Aug 1;301(5633):640-3
12855817
Nat Med. 2008 Dec;14(12):1318-9
19057556
J Immunol. 2007 Mar 1;178(5):2979-86
17312143
Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):588-93
9435236
Cardiovasc Ther. 2009 Summer;27(2):117-23
19426249
Circulation. 2009 Oct 6;120(14):1401-14
19770394
Curr Biol. 2000 Sep 21;10(18):1139-42
10996797
Drug Discov Today Technol. 2004 Dec;1(4):337-41
24981612
Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15416-21
15492225
Int J Biochem Cell Biol. 2010 Apr;42(4):506-18
19837184
Circ Res. 2009 Oct 23;105(9):912-20
19762681
J Biol Chem. 2005 Jul 15;280(28):26152-9
15849357
Curr Opin Immunol. 2008 Feb;20(1):39-48
18083507
Cardiovasc Res. 2009 Dec 1;84(3):442-51
19586942
Biochem Biophys Res Commun. 2009 Oct 30;388(4):621-5
19686699
Nat Rev Immunol. 2007 May;7(5):353-64
17457343
Nat Immunol. 2002 Apr;3(4):392-8
11896392
Front Biosci (Elite Ed). 2009 Jun 01;1:476-87
19482661
J Med Chem. 2008 Mar 13;51(5):1189-202
18275134
Eur J Immunol. 2006 Mar;36(3):742-53
16482509
Nat Rev Genet. 2001 Apr;2(4):256-67
11283698
J Immunol. 2007 Mar 1;178(5):2655-60
17312106
Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3533-8
14982987
Nat Immunol. 2005 Nov;6(11):1087-95
16186825
Science. 2008 Aug 1;321(5889):691-6
18669862
Nat Immunol. 2006 Oct;7(10):1074-81
16964262
Science. 1999 May 21;284(5418):1313-8
10334979
Nature. 2000 Nov 2;408(6808):111-5
11081518
Pharmacol Rev. 2009 Jun;61(2):177-97
19474110
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2953-8
16477040
J Exp Med. 2003 Oct 6;198(7):1043-55
14517278
Genomics. 2001 Jun 1;74(2):234-44
11386760
Nat Rev Immunol. 2005 Oct;5(10):749-59
16175180
J Cardiovasc Pharmacol. 2010 Apr;55(4):385-90
20125030
Cell. 2006 Feb 24;124(4):815-22
16497590
Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14459-63
10588727
J Biol Chem. 2007 Mar 2;282(9):6075-89
17197697
Curr Opin Mol Ther. 2008 Feb;10(1):21-31
18228178
Immunol Rev. 2008 Dec;226:10-8
19161412
J Biol Chem. 2005 Apr 22;280(16):15809-14
15755740
Adv Immunol. 2009;102:95-133
19477320
Nat Immunol. 2001 Sep;2(9):835-41
11526399
Cell Mol Immunol. 2007 Feb;4(1):31-41
17349209
Nature. 2001 Jul 19;412(6844):346-51
11460167
Nat Immunol. 2008 Apr;9(4):361-8
18297073
PLoS Comput Biol. 2009 Feb;5(2):e1000292
19229310
EMBO J. 2000 Apr 3;19(7):1576-86
10747026
J Immunol. 2002 Dec 15;169(12):6668-72
12471095
Int Immunol. 2009 Apr;21(4):317-37
19246554
J Leukoc Biol. 1998 Jun;63(6):650-7
9620655
Nat Immunol. 2003 Nov;4(11):1144-50
14556004
J Immunol. 2001 Nov 15;167(10):5887-94
11698465
Cell. 2006 Feb 24;124(4):783-801
16497588
Trends Immunol. 2003 Jun;24(6):286-90
12810098
Nature. 2002 Nov 21;420(6913):324-9
12447441
Immunity. 1998 Jul;9(1):143-50
9697844
Cell. 2006 Jun 2;125(5):943-55
16751103
Nat Rev Immunol. 2004 Jul;4(7):512-20
15229470
J Leukoc Biol. 2007 Oct;82(4):801-10
17548806
Br J Pharmacol. 2005 Aug;145(8):1093-102
15937518
Nat Immunol. 2004 Jul;5(7):730-7
15208624
J Biol Chem. 2008 May 2;283(18):11861-5
18332149
Trends Pharmacol Sci. 2009 Jun;30(6):313-21
19446347
Nat Immunol. 2004 Oct;5(10):1061-8
15361868
Curr Opin Pharmacol. 2008 Feb;8(1):8-13
17974478
J Immunol. 2005 Jul 1;175(1):494-500
15972684
Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):13-20
8552589
Nat Rev Immunol. 2005 Jun;5(6):446-58
15928677
J Immunol. 2005 Dec 1;175(11):7484-95
16301656
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18631-5
18006661
Oncogene. 1990 Jul;5(7):1095-7
2374694
Nat Med. 2007 May;13(5):552-9
17479101
Immunol Rev. 2009 Jul;230(1):9-21
19594626
Acta Biochim Pol. 2008;55(4):629-47
19081854
J Biol Chem. 2004 Apr 2;279(14):13677-88
14734551
Cell Death Differ. 2006 May;13(5):816-25
16410796
J Immunol. 2009 Jan 1;182(1):572-80
19109190
Inflamm Bowel Dis. 2005 Aug;11(8):713-9
16043985
Science. 1998 Dec 11;282(5396):2085-8
9851930
Proc Natl Acad Sci U S A. 2009 Jan 20;106(3):870-5
19139407
Immunity. 2005 Nov;23(5):479-90
16286016
Ann N Y Acad Sci. 2008 Nov;1143:21-34
19076342
J Biol Chem. 2000 Jun 2;275(22):17051-7
10748117
Oncogene. 1996 Dec 5;13(11):2467-75
8957090
Immunity. 2008 Aug 15;29(2):182-91
18701082
J Biol Chem. 2004 Jul 23;279(30):31664-70
15123616
Immunity. 1999 Jul;11(1):115-22
10435584
J R Soc Interface. 2006 Apr 22;3(7):215-33
16849232
Cytokine. 2008 Apr;42(1):1-7
18249132
Nature. 2002 May 16;417(6886):254-9
12015594
Annu Rev Immunol. 2009;27:519-50
19302047
J Exp Med. 2007 Oct 1;204(10):2407-22
17893200
Int Immunopharmacol. 2007 Oct;7(10):1271-85
17673142
J Biol Chem. 2009 Sep 11;284(37):25404-11
19592493
J Biol Chem. 1995 Jun 9;270(23):13757-65
7775431