TNFA deletion alters apoptosis as well as caspase 3 and 4 expression during otitis media.
BACKGROUND
Tumor necrosis factor (TNFA) is the canonical member of the TNF superfamily, which plays a major role in both inflammation and apoptosis. To evaluate the role of TNFs in otitis media (OM), the most common disease of childhood, we evaluated middle ear (ME) expression of genes encoding the TNF and TNF receptor superfamilies during bacterial OM in the mouse, characterized OM in TNFA-deficient mice, and assessed apoptosis during OM in normal versus TNF-deficient MEs.


RESULTS
TNFs and TNF receptors were broadly regulated during OM, with TNFA showing the highest level of up-regulation. TNF deficient mice exhibited mucosal hyperplasia even in the absence of infection and exuberant growth of the mucosa during OM, including the formation of mucosal polyps. Mucosal recovery during OM was also delayed, in parallel with a delay in mucosal apoptosis and reduced caspase gene expression.


CONCLUSIONS
The TNF and TNF receptor superfamilies mediate both inflammation and apoptosis during OM. TNF appears to be critical for the maintenance of mucosal architecture in both the normal and infected ME, since excessive accumulation of mucosal tissue is seen in TNFA-/- MEs both before and after bacterial inoculation of the ME. TNFA is also required for appropriate regulation of caspase genes.
Department of Otorhinolaryngology, Head and Neck Surgery Klinikum Bielefeld, Academic Teaching Hospital University of Münster, Bielefeld, Germany.
Joerg
J
Ebmeyer
Anke
A
Leichtle
Michelle
M
Hernandez
Umay
U
Ebmeyer
Jacob
J
Husseman
Kwang
K
Pak
Holger
H
Sudhoff
David
D
Broide
Stephen I
SI
Wasserman
Allen F
AF
Ryan
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D053471:Caspases, Initiator; D004432:Ear, Middle / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010033:Otitis Media / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha
D014409:Tumor Necrosis Factor-alpha; C505409:Casp3 protein, mouse; C101136:Casp4 protein, mouse; D053148:Caspase 3; D020169:Caspases; D053471:Caspases, Initiator
Nat Rev Mol Cell Biol. 2004 Nov;5(11):897-907
15520809
J Biol Chem. 1996 May 31;271(22):12687-90
8663110
BMC Genet. 2002 Jun 27;3:11
12102730
Rev Gastroenterol Disord. 2004;4 Suppl 3:S10-7
15580148
Laryngoscope. 1991 Mar;101(3):271-5
2000014
Nat Immunol. 2007 Jun;8(6):601-9
17496895
Methods Cell Biol. 2008;87:153-65
18485296
Apoptosis. 2010 Oct;15(10):1211-22
20514521
Immunity. 2001 Nov;15(5):837-46
11728344
J Biol Chem. 1999 Mar 5;274(10):6056-61
10037686
Immunity. 1995 Dec;3(6):673-82
8777713
Curr Biol. 1999 Feb 25;9(4):215-8
10074428
News Physiol Sci. 2003 Jun;18:89-94
12750442
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W627-32
15980550
J Biol Chem. 2002 Dec 20;277(51):50054-61
12393901
J Biol Chem. 2000 May 19;275(20):15336-42
10809768
Invest Ophthalmol Vis Sci. 2003 May;44(5):2184-91
12714660
J Biol Chem. 1998 Jun 5;273(23):14363-7
9603945
J Innate Immun. 2010;2(3):216-27
20375550
J Immunol. 2010 Mar 15;184(6):3087-97
20164426
J Allergy Clin Immunol. 2005 Nov;116(5):1129-35
16275387
Immunity. 1999 Dec;11(6):783-93
10626900
Rom J Gastroenterol. 2003 Sep;12(3):207-14
14502322
Eur Cytokine Netw. 2002 Apr-Jun;13(2):161-72
12101072
J Clin Invest. 1998 Sep 15;102(6):1142-51
9739048
Eur Arch Otorhinolaryngol. 2000;257(6):323-6
10993552
Oncogene. 1997 Jul 17;15(3):285-90
9233763
J Cell Sci. 2009 Jun 15;122(Pt 12):1939-46
19494121
Arch Otolaryngol Head Neck Surg. 1995 Aug;121(8):865-9
7619411
Science. 2002 May 31;296(5573):1634-5
12040173
Pediatr Infect Dis J. 1999 Mar;18(3):301-3
10093960
J Exp Med. 1999 Jun 7;189(11):1747-56
10359578
Brain Res. 2006 May 26;1091(1):3-8
16764829
Curr Allergy Asthma Rep. 2001 May;1(3):262-7
11892044
Laryngoscope. 2001 Apr;111(4 Pt 1):728-33
11359148
Eur J Immunol. 1994 Sep;24(9):2219-27
8088337
Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1751-6
11172023
Infect Immun. 2000 Jul;68(7):4024-31
10858218
Ann Otol Rhinol Laryngol. 1986 May-Jun;95(3 Pt 1):242-9
3717850
J Exp Med. 1996 Oct 1;184(4):1397-411
8879212
J Exp Med. 1994 Aug 1;180(2):757-62
7913952
J Biol Chem. 2007 Oct 26;282(43):31601-9
17702740
J Clin Invest. 2007 Mar;117(3):803-11
17290304
Nat Rev Immunol. 2003 Sep;3(9):745-56
12949498
Hear Res. 2005 Sep;207(1-2):110-6
15978756
J Infect Dis. 1993 Nov;168(5):1277-81
8228363
J Infect Dis. 2008 Dec 15;198(12):1862-9
18986247
J Infect Dis. 2000 Sep;182(3):882-7
10950784
APMIS. 2003 Oct;111(10):989-94
14616553