title: Interleukin-1β mediates virus-induced m2 muscarinic receptor dysfunction and airway hyperreactivity.
abstract: Respiratory viral infections are associated with the majority of asthma attacks. Inhibitory M2 receptors on parasympathetic nerves, which normally limit acetylcholine (ACh) release, are dysfunctional after respiratory viral infection. Because IL-1β is up-regulated during respiratory viral infections, we investigated whether IL-1β mediates M2 receptor dysfunction during parainfluenza virus infection. Virus-infected guinea pigs were pretreated with the IL-1β antagonist anakinra. In the absence of anakinra, viral infection increased bronchoconstriction in response to vagal stimulation but not to intravenous ACh, and neuronal M2 muscarinic receptors were dysfunctional. Pretreatment with anakinra prevented virus-induced increased bronchoconstriction and M2 receptor dysfunction. Anakinra did not change smooth muscle M3 muscarinic receptor response to ACh, lung viral loads, or blood and bronchoalveolar lavage leukocyte populations. Respiratory virus infection decreased M2 receptor mRNA expression in parasympathetic ganglia extracted from infected animals, and this was prevented by blocking IL-1β or TNF-α. Treatment of SK-N-SH neuroblastoma cells or primary cultures of guinea pig parasympathetic neurons with IL-1β directly decreased M2 receptor mRNA, and this was not synergistic with TNF-α treatment. Treating guinea pig trachea segment with TNF-α or IL-1β in vitro increased tracheal contractions in response to activation of airway nerves by electrical field stimulation. Blocking IL-1β during TNF-α treatment prevented this hyperresponsiveness. These data show that virus-induced hyperreactivity and M2 dysfunction involves IL-1β and TNF-α, likely in sequence with TNF-α causing production of IL-1β.
authors.affiliation: 1 Department of Molecular Microbiology and Immunology, and.
authors.forename: Abby E
authors.initials: AE
authors.lastname: Rynko
authors.forename: Allison D
authors.initials: AD
authors.lastname: Fryer
authors.forename: David B
authors.initials: DB
authors.lastname: Jacoby
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control / Q000821:virology; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006168:Guinea Pigs; D054884:Host-Pathogen Interactions; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000294:innervation / Q000378:metabolism* / Q000503:physiopathology / Q000821:virology; D010252:Paramyxoviridae / Q000276:immunology / Q000472:pathogenicity*; D018184:Paramyxoviridae Infections / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology / Q000821:virology; D010275:Parasympathetic Nervous System / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*; D012141:Respiratory Tract Infections / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology / Q000821:virology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D043585:Receptor, Muscarinic M2; D014409:Tumor Necrosis Factor-alpha
keywords: IL-1β; TNF-α; asthma; parainfluenza virus; parasympathetic nerves
references.citation: J Appl Physiol (1985). 1991 Dec;71(6):2255-61
references.pmid: 1778920
references.citation: Arch Intern Med. 1998 Dec 7-21;158(22):2453-9
references.pmid: 9855383
references.citation: Pulm Pharmacol. 1990;3(1):47-51
references.pmid: 2152027
references.citation: J Allergy Clin Immunol. 2007 Jun;119(6):1337-48
references.pmid: 17416409
references.citation: J Virol. 2006 Jan;80(1):537-40
references.pmid: 16352577
references.citation: Am J Respir Cell Mol Biol. 2008 Dec;39(6):730-8
references.pmid: 18617681
references.citation: Curr Opin Allergy Clin Immunol. 2006 Feb;6(1):43-50
references.pmid: 16505611
references.citation: Thorax. 2005 Dec;60(12):1012-8
references.pmid: 16166100
references.citation: Curr Neurobiol. 2011 Apr;2(1):23-29
references.pmid: 23226931
references.citation: J Immunol. 1992 Nov 1;149(9):3078-82
references.pmid: 1401932
references.citation: Ann Allergy Asthma Immunol. 2004 Jan;92(1):32-9
references.pmid: 14756462
references.citation: J Virol. 2009 Jul;83(13):6837-48
references.pmid: 19357175
references.citation: BMJ. 1995 May 13;310(6989):1225-9
references.pmid: 7767192
references.citation: Br J Pharmacol. 2009 Jan;156(1):201-10
references.pmid: 19134001
references.citation: N Engl J Med. 2006 Feb 16;354(7):697-708
references.pmid: 16481637
references.citation: J Allergy Clin Immunol. 1992 May;89(5):958-67
references.pmid: 1374772
references.citation: Am J Physiol Lung Cell Mol Physiol. 2004 Jun;286(6):L1255-9
references.pmid: 15136297
references.citation: Br J Pharmacol. 1984 Dec;83(4):973-8
references.pmid: 6518347
references.citation: Am J Physiol. 1991 Oct;261(4 Pt 1):L327-33
references.pmid: 1928368
references.citation: Am Rev Respir Dis. 1980 Jul;122(1):3-10
references.pmid: 7406340
references.citation: Eur J Pharmacol. 1992 Mar 31;213(3):331-6
references.pmid: 1377630
references.citation: J Leukoc Biol. 1996 Jul;60(1):125-8
references.pmid: 8699116
references.citation: J Allergy Clin Immunol. 2006 Mar;117(3):496-506; quiz 507
references.pmid: 16522446
references.citation: J Allergy Clin Immunol. 2006 Mar;117(3):508-11
references.pmid: 16522447
references.citation: Am Rev Respir Dis. 1976 Feb;113(2):131-9
references.pmid: 1247226
references.citation: Br J Pharmacol. 1991 Jan;102(1):267-71
references.pmid: 1646059
references.citation: J Appl Physiol (1985). 1989 Dec;67(6):2461-5
references.pmid: 2606854
references.citation: Br J Pharmacol. 2011 Sep;164(2b):444-52
references.pmid: 21457223
references.citation: Front Microbiol. 2010 Nov 15;1:124
references.pmid: 21687760
references.citation: J Biol Chem. 1996 Dec 20;271(51):32586-92
references.pmid: 8955085
references.citation: J Appl Physiol (1985). 2002 Apr;92(4):1417-22
references.pmid: 11896005
references.citation: Am Rev Respir Dis. 1969 Aug;100(2):141-6
references.pmid: 5805258
references.citation: J Gen Virol. 1995 May;76 ( Pt 5):1251-4
references.pmid: 7730810
references.citation: Am J Respir Crit Care Med. 1995 Nov;152(5 Pt 1):1474-7
references.pmid: 7582279
references.citation: Annu Rev Med. 1984;35:451-67
references.pmid: 6144287
references.citation: J Allergy Clin Immunol. 2006 Mar;117(3):522-43
references.pmid: 16522450
references.citation: Am J Respir Crit Care Med. 1996 Oct;154(4 Pt 1):1061-6
references.pmid: 8887608
references.citation: J Clin Invest. 1998 Jul 1;102(1):242-8
references.pmid: 9649578
references.citation: Br J Pharmacol. 1994 Jun;112(2):588-94
references.pmid: 8075876