title: Dual functionality of interleukin-1 family cytokines: implications for anti-interleukin-1 therapy.
abstract: Dysregulated inflammation contributes to disease pathogenesis in both the periphery and the brain. Cytokines are coordinators of inflammation and were originally defined as secreted mediators, released from expressing cells to activate plasma membrane receptors on responsive cells. However, a group of cytokines is now recognized as having dual functionality. In addition to their extracellular effects, these cytokines act inside the nuclei of cytokine-expressing or cytokine-responsive cells. Interleukin-1 (IL-1) family cytokines are key pro-inflammatory mediators, and blockade of the IL-1 system in inflammatory diseases is an attractive therapeutic goal. All current therapies target IL-1 extracellular actions. Here we review evidence that suggests IL-1 family members have dual functionality. Several IL-1 family members have been detected inside the nuclei of IL-1-expressing or IL-1-responsive cells, and intranuclear IL-1 is reported to regulate gene transcription and mRNA splicing. However, further work is required to determine the impact of IL-1 intranuclear actions on disease pathogenesis. The intranuclear actions of IL-1 family members represent a new and potentially important area of IL-1 biology and may have implications for the future development of anti-IL-1 therapies.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK. nadia.luheshi-2@manchester.ac.uk
authors.forename: N M
authors.initials: NM
authors.lastname: Luheshi
authors.forename: N J
authors.initials: NJ
authors.lastname: Rothwell
authors.forename: D
authors.initials: D
authors.lastname: Brough
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000502:physiology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D012326:RNA Splicing; D014158:Transcription, Genetic
chemical_list: D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2434-9
references.pmid: 14983027
references.citation: Nat Rev Mol Cell Biol. 2003 Aug;4(8):605-12
references.pmid: 12923522
references.citation: Glia. 2006 Apr 1;53(5):551-6
references.pmid: 16374779
references.citation: J Appl Physiol (1985). 1991 Dec;71(6):2412-8
references.pmid: 1778940
references.citation: J Leukoc Biol. 2000 Jun;67(6):757-66
references.pmid: 10857846
references.citation: J Neurochem. 2006 Sep;98(5):1379-89
references.pmid: 16771830
references.citation: J Neurochem. 2000 Feb;74(2):457-71
references.pmid: 10646496
references.citation: Eur J Biochem. 2003 May;270(10):2109-19
references.pmid: 12752430
references.citation: Nature. 1992 Apr 30;356(6372):768-74
references.pmid: 1574116
references.citation: J Cell Sci. 2001 Jul;114(Pt 13):2363-73
references.pmid: 11559745
references.citation: Curr Opin Immunol. 2002 Feb;14(1):117-22
references.pmid: 11790541
references.citation: Am J Physiol Heart Circ Physiol. 2007 Jun;292(6):H2927-34
references.pmid: 17293495
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14501-6
references.pmid: 16971486
references.citation: Nat Rev Mol Cell Biol. 2003 Oct;4(10):757-66
references.pmid: 14570049
references.citation: Eur J Immunol. 1999 Mar;29(3):781-8
references.pmid: 10092080
references.citation: Nature. 2007 Nov 29;450(7170):600-1
references.pmid: 18046368
references.citation: EMBO J. 1984 Aug;3(8):1831-6
references.pmid: 6207019
references.citation: J Neurosci. 2001 Aug 1;21(15):5528-34
references.pmid: 11466424
references.citation: FASEB J. 2003 Feb;17(2):203-13
references.pmid: 12554699
references.citation: EMBO J. 1997 Nov 3;16(21):6535-47
references.pmid: 9351834
references.citation: Am J Physiol. 1999 Mar;276(3):H901-12
references.pmid: 10070073
references.citation: Glia. 1999 Feb 15;25(4):311-23
references.pmid: 10028914
references.citation: J Immunol. 1995 Nov 1;155(9):4467-75
references.pmid: 7594609
references.citation: Stroke. 1995 Apr;26(4):676-80; discussion 681
references.pmid: 7709417
references.citation: Science. 1999 Jul 9;285(5425):248-51
references.pmid: 10398600
references.citation: J Immunol. 2004 Jul 15;173(2):1202-8
references.pmid: 15240711
references.citation: Biochem J. 1989 Dec 15;264(3):813-22
references.pmid: 2533500
references.citation: J Immunol. 1990 Feb 15;144(4):1295-303
references.pmid: 2137488
references.citation: Neuropharmacology. 2007 Oct;53(5):638-42
references.pmid: 17845807
references.citation: Cytokine Growth Factor Rev. 2002 Aug-Oct;13(4-5):323-40
references.pmid: 12220547
references.citation: Ann Rheum Dis. 2002 Jul;61(7):577-9
references.pmid: 12079894
references.citation: J Exp Med. 1972 Jul 1;136(1):128-42
references.pmid: 5033417
references.citation: Proc Natl Acad Sci U S A. 1991 May 1;88(9):3681-5
references.pmid: 1827201
references.citation: J Biol Chem. 1988 Jun 15;263(17):8261-9
references.pmid: 2967293
references.citation: EMBO J. 1990 May;9(5):1503-10
references.pmid: 2328723
references.citation: J Immunol. 1998 Mar 1;160(5):2469-77
references.pmid: 9498792
references.citation: J Biol Chem. 1997 Mar 21;272(12):7727-31
references.pmid: 9065432
references.citation: Cancer Res. 2007 Feb 1;67(3):1062-71
references.pmid: 17283139
references.citation: Nat Rev Immunol. 2007 Jan;7(1):31-40
references.pmid: 17186029
references.citation: Blood. 1996 Mar 15;87(6):2095-147
references.pmid: 8630372
references.citation: Cell Growth Differ. 1991 Jul;2(7):311-5
references.pmid: 1664234
references.citation: Cell Immunol. 2005 Sep;237(1):17-27
references.pmid: 16289056
references.citation: Trends Biochem Sci. 2001 Mar;26(3):167-74
references.pmid: 11246022
references.citation: Cytokine Growth Factor Rev. 1997 Dec;8(4):253-65
references.pmid: 9620641
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):10008-13
references.pmid: 12913118
references.citation: Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):508-13
references.pmid: 9012814
references.citation: J Immunol. 2004 Feb 1;172(3):1654-60
references.pmid: 14734747
references.citation: J Infect Dis. 2006 May 15;193(10):1419-26
references.pmid: 16619190
references.citation: Exp Cell Res. 1995 Apr;217(2):355-62
references.pmid: 7698236
references.citation: J Cell Sci. 2003 Aug 1;116(Pt 15):3089-98
references.pmid: 12799413
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10913-8
references.pmid: 18667700
references.citation: Int Immunol. 2001 Dec;13(12):1471-8
references.pmid: 11717188
references.citation: Trends Immunol. 2001 Oct;22(10):533-6
references.pmid: 11574261
references.citation: FASEB J. 2007 Dec;21(14):3904-16
references.pmid: 17628015
references.citation: Biochem Biophys Res Commun. 1992 Sep 16;187(2):1166-71
references.pmid: 1388356
references.citation: Nat Rev Immunol. 2005 Apr;5(4):331-42
references.pmid: 15803152
references.citation: Science. 2001 Aug 31;293(5535):1653-7
references.pmid: 11533489
references.citation: J Cell Sci. 2003 Jul 1;116(Pt 13):2687-96
references.pmid: 12746488
references.citation: Trends Immunol. 2005 Nov;26(11):587-95
references.pmid: 16168711
references.citation: Nat Rev Drug Discov. 2004 Apr;3(4):330-9
references.pmid: 15060528
references.citation: J Immunol. 2008 Jan 1;180(1):402-8
references.pmid: 18097041
references.citation: PLoS One. 2008 Oct 06;3(10):e3331
references.pmid: 18836528
references.citation: Cytokine. 1996 Jun;8(6):460-7
references.pmid: 8818542
references.citation: J Cell Sci. 2003 Dec 15;116(Pt 24):4871-81
references.pmid: 14625381
references.citation: Nat Rev Drug Discov. 2008 Oct;7(10):827-40
references.pmid: 18827826
references.citation: J Exp Med. 1995 Aug 1;182(2):623-8
references.pmid: 7629520
references.citation: Nat Clin Pract Rheumatol. 2006 Jan;2(1):44-52
references.pmid: 16932651
references.citation: J Cereb Blood Flow Metab. 1996 Sep;16(5):932-40
references.pmid: 8784237
references.citation: Am J Pathol. 2008 Oct;173(4):1229-42
references.pmid: 18787100
references.citation: Int J Immunopharmacol. 1992 Apr;14(3):401-11
references.pmid: 1618594
references.citation: Cytokine. 2006 Mar 7;33(5):274-80
references.pmid: 16564702
references.citation: Proc Natl Acad Sci U S A. 1997 May 27;94(11):5814-9
references.pmid: 9159157
references.citation: Eur J Immunol. 1989 Sep;19(9):1531-6
references.pmid: 2792179
references.citation: Nature. 2002 Dec 19-26;420(6917):885-91
references.pmid: 12490963
references.citation: J Immunol. 2008 Apr 15;180(8):5477-82
references.pmid: 18390730
references.citation: Adv Exp Med Biol. 2000;479:185-202
references.pmid: 10897420
references.citation: Handb Exp Pharmacol. 2008;(183):21-50
references.pmid: 18071653
references.citation: Science. 1993 Jul 23;261(5120):472-5
references.pmid: 8332913
references.citation: Nature. 1986 Nov 20-26;324(6094):266-8
references.pmid: 2946959
references.citation: J Immunol. 2005 Mar 15;174(6):3608-16
references.pmid: 15749898
references.citation: Cytokine. 2001 Aug 7;15(3):122-37
references.pmid: 11554782
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):282-7
references.pmid: 17185418
references.citation: Atherosclerosis. 2007 Nov;195(1):31-8
references.pmid: 17173923
references.citation: Traffic. 2009 Jan;10(1):16-25
references.pmid: 18939951
references.citation: Proc Natl Acad Sci U S A. 1990 Jul;87(14):5548-52
references.pmid: 2115174
references.citation: J Biol Chem. 2001 Jan 12;276(2):1299-303
references.pmid: 11032842
references.citation: Eur J Neurosci. 2000 Jul;12(7):2623-33
references.pmid: 10947836
references.citation: J Cell Physiol. 1992 Aug;152(2):223-31
references.pmid: 1639857
references.citation: J Neurosci. 2003 Sep 24;23(25):8692-700
references.pmid: 14507968
references.citation: Immunology. 2001 Dec;104(4):402-9
references.pmid: 11899425
references.citation: J Allergy Clin Immunol. 1991 Aug;88(2):244-56
references.pmid: 1831824
references.citation: Mol Cell Biol. 1994 Mar;14(3):1845-51
references.pmid: 8114717
references.citation: J Immunol. 1998 Aug 15;161(4):1997-2003
references.pmid: 9712072
references.citation: EMBO Rep. 2002 Oct;3(10):995-1001
references.pmid: 12231511
references.citation: J Immunol. 1987 Nov 15;139(10):3406-15
references.pmid: 3316383
references.citation: EMBO J. 1991 Oct;10(10):2821-32
references.pmid: 1833184
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2904-8
references.pmid: 16477014
references.citation: Bioessays. 2003 Apr;25(4):401-9
references.pmid: 12655647
references.citation: Stroke. 2000 Jul;31(7):1735-43
references.pmid: 10884481
references.citation: J Biol Chem. 1993 Oct 15;268(29):22100-4
references.pmid: 8408068
references.citation: J Biol Chem. 2004 Feb 6;279(6):4017-26
references.pmid: 14612453
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2645-50
references.pmid: 12598651
references.citation: Cytokine. 1994 Nov;6(6):597-601
references.pmid: 7893968
references.citation: J Biol Chem. 1987 Mar 5;262(7):2941-4
references.pmid: 2950091
references.citation: J Cereb Blood Flow Metab. 1998 Feb;18(2):180-5
references.pmid: 9469161
references.citation: J Immunol. 1987 May 1;138(9):2906-12
references.pmid: 2952728
references.citation: Nat Clin Pract Rheumatol. 2008 Jan;4(1):34-42
references.pmid: 18172447
references.citation: J Immunol. 1999 Oct 1;163(7):3969-75
references.pmid: 10490999
references.citation: J Cell Biol. 1975 Sep;66(3):652-7
references.pmid: 1158974
references.citation: Zoolog Sci. 2005 Aug;22(8):891-6
references.pmid: 16141702
references.citation: J Biol Chem. 1997 Nov 7;272(45):28202-5
references.pmid: 9353269
references.citation: J Exp Med. 1998 May 4;187(9):1463-75
references.pmid: 9565638
references.citation: Nature. 2008 Mar 6;452(7183):103-7
references.pmid: 18288107
references.citation: Infect Immun. 2008 Mar;76(3):942-51
references.pmid: 18086816
references.citation: Nat Genet. 1999 Jul;22(3):276-80
references.pmid: 10391216
references.citation: J Neurol Neurosurg Psychiatry. 2005 Oct;76(10):1366-72
references.pmid: 16170078
references.citation: Proc Natl Acad Sci U S A. 1986 Nov;83(22):8749-53
references.pmid: 3490671
references.citation: Cytokine. 2005 Nov 3;32(3-4):163-70
references.pmid: 16246569
references.citation: Brain Res Bull. 1992 Aug;29(2):243-6
references.pmid: 1388088
references.citation: Eur Respir J Suppl. 2001 Dec;34:50s-59s
references.pmid: 12392035
references.citation: Cytokine. 2005 Jul 21;31(2):153-60
references.pmid: 15923123
references.citation: J Neurosci. 1999 Jun 15;19(12):5054-65
references.pmid: 10366638
references.citation: Rheumatology (Oxford). 2004 Jun;43 Suppl 3:iii2-iii9
references.pmid: 15150426
references.citation: Clin Cancer Res. 2006 Feb 15;12(4):1088-96
references.pmid: 16489061
references.citation: Am J Pathol. 1990 Nov;137(5):1173-85
references.pmid: 2240164
references.citation: J Physiol. 1990 Sep;428:299-312
references.pmid: 2231415
references.citation: J Immunol. 1996 Nov 15;157(10):4576-83
references.pmid: 8906836
references.citation: Immunity. 2005 Nov;23(5):479-90
references.pmid: 16286016
references.citation: Nat Rev Mol Cell Biol. 2007 Mar;8(3):195-208
references.pmid: 17287812
references.citation: J Rheumatol. 2004 Oct;31(10):1946-54
references.pmid: 15468358
references.citation: Cytokine. 2003 Jul;23(1-2):31-40
references.pmid: 12901852
references.citation: J Immunol. 1997 Jun 15;158(12):5949-57
references.pmid: 9190949
references.citation: Nature. 1997 Mar 13;386(6621):190-4
references.pmid: 9062193
references.citation: J Immunol. 2007 Nov 15;179(10):6933-42
references.pmid: 17982084
references.citation: Nat Rev Immunol. 2005 Aug;5(8):629-40
references.pmid: 16034365