title: Anti-inflammatory effects of tumour necrosis factor (TNF)-alpha are mediated via TNF-R2 (p75) in tolerogenic transforming growth factor-beta-treated antigen-presenting cells.
abstract: Exposure of macrophages to transforming growth factor (TGF)-beta is known to alter their functional phenotype such that antigen presentation by these cells leads to tolerance rather than an inflammatory immune response. Typically, eye-derived antigen-presenting cells (APCs) exposed to TGF-beta in the local environment are known to induce a form of peripheral tolerance and protect the eye from inflammatory immune effector-mediated damage. In response to TGF-beta, APCs increase their expression of tumour necrosis factor (TNF)-alpha and TNF receptor 2 (TNF-R2). Although TNF-alpha has been implicated in tolerance and the associated regulation of the inflammatory immune response, its source and the receptors involved remain unclear. In this report we determined the contribution of TNF-alpha and TNF-R2 expressed by TGF-beta-treated APCs to their anti-inflammatory tolerogenic effect. Our results indicate that APC-derived TNF-alpha is essential for the ability of APCs to regulate the immune response and their IL-12 secretion. Moreover, in the absence of TNF-R2, APCs exposed to TGF-beta failed to induce tolerance or regulatory cells known to participate in this tolerance. Also, blocking of TNF-R1 signalling enhanced the ability of the APCs to secrete increased TGF-beta in response to TGF-beta exposure. Together our results support an anti-inflammatory role of TNF-alpha in regulation of an immune response by TGF-beta-treated APCs and suggest that TNF-R2 contributes significantly to this role.
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. sharmila.masli@schepens.harvard.edu
authors.forename: Sharmila
authors.initials: S
authors.lastname: Masli
authors.forename: Bruce
authors.initials: B
authors.lastname: Turpie
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D007108:Immune Tolerance / Q000276:immunology; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D047889:Receptors, Tumor Necrosis Factor, Type II; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13806-11
references.pmid: 9811882
references.citation: Ann N Y Acad Sci. 1998 Nov 17;859:290-4
references.pmid: 9928407
references.citation: Cell. 1995 Dec 1;83(5):793-802
references.pmid: 8521496
references.citation: FEBS Lett. 2002 Mar 27;515(1-3):119-26
references.pmid: 11943206
references.citation: J Exp Med. 2001 Feb 19;193(4):427-34
references.pmid: 11181695
references.citation: Eur J Immunol. 1997 Jul;27(7):1648-56
references.pmid: 9247573
references.citation: J Immunol. 1998 Jan 15;160(2):943-52
references.pmid: 9551933
references.citation: J Neurosci Res. 1996 Aug 15;45(4):322-33
references.pmid: 8872892
references.citation: Invest Ophthalmol Vis Sci. 2000 Jun;41(7):1803-11
references.pmid: 10845601
references.citation: Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8093-8
references.pmid: 9223320
references.citation: J Immunol. 1997 Dec 15;159(12):6276-82
references.pmid: 9550432
references.citation: Biochem J. 2001 Nov 1;359(Pt 3):525-35
references.pmid: 11672426
references.citation: Eur J Immunol. 1992 Jan;22(1):165-73
references.pmid: 1530916
references.citation: Nature. 1995 Sep 28;377(6547):348-51
references.pmid: 7566090
references.citation: Nature. 1997 Feb 20;385(6618):729-33
references.pmid: 9034190
references.citation: Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9292-6
references.pmid: 1718003
references.citation: Clin Infect Dis. 2005 Aug 1;41 Suppl 3:S199-203
references.pmid: 15983900
references.citation: J Immunol. 2000 Feb 15;164(4):1722-9
references.pmid: 10657616
references.citation: J Immunol. 1998 Feb 15;160(4):1589-97
references.pmid: 9469414
references.citation: J Immunol. 2004 Feb 15;172(4):1991-5
references.pmid: 14764660
references.citation: J Immunol. 1993 Nov 1;151(9):4637-41
references.pmid: 8409424
references.citation: J Cell Sci. 2002 Jul 1;115(Pt 13):2757-70
references.pmid: 12077366
references.citation: Int Immunol. 2006 May;18(5):689-99
references.pmid: 16569680
references.citation: J Immunol. 1995 Nov 15;155(10):4661-8
references.pmid: 7594465
references.citation: Biochem Pharmacol. 2001 Mar 15;61(6):749-59
references.pmid: 11266661
references.citation: J Immunol. 1996 Sep 15;157(6):2348-57
references.pmid: 8805632
references.citation: Trends Cell Biol. 1995 Oct;5(10):392-9
references.pmid: 14732063
references.citation: Exp Dermatol. 1999 Dec;8(6):495-500
references.pmid: 10597139
references.citation: Eur J Immunol. 1999 Feb;29(2):626-32
references.pmid: 10064079
references.citation: J Immunol. 2002 Mar 1;168(5):2264-73
references.pmid: 11859114
references.citation: Br J Rheumatol. 1992 May;31(5):293-8
references.pmid: 1581770
references.citation: J Rheumatol. 2003 Oct;30(10):2287-91
references.pmid: 14528531
references.citation: J Exp Med. 1997 Oct 6;186(7):1119-28
references.pmid: 9314560
references.citation: J Immunol. 1992 Sep 1;149(5):1531-8
references.pmid: 1387141
references.citation: J Immunol. 2001 May 1;166(9):5619-28
references.pmid: 11313402
references.citation: Invest Ophthalmol Vis Sci. 2000 May;41(6):1410-21
references.pmid: 10798657
references.citation: Am J Pathol. 1999 May;154(5):1417-22
references.pmid: 10329594
references.citation: Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):570-5
references.pmid: 9435233
references.citation: J Biol Chem. 1998 Aug 28;273(35):22800-6
references.pmid: 9712914
references.citation: J Immunol. 2005 Nov 15;175(10):6286-93
references.pmid: 16272279
references.citation: Invest Ophthalmol Vis Sci. 1994 Apr;35(5):2643-51
references.pmid: 8163352
references.citation: Cytokine. 2006 Feb 21;33(4):231-7
references.pmid: 16542849
references.citation: Immunology. 1999 Mar;96(3):372-80
references.pmid: 10233718
references.citation: J Immunol. 2006 Aug 1;177(3):1618-27
references.pmid: 16849470
references.citation: J Exp Med. 1995 Feb 1;181(2):607-17
references.pmid: 7836916
references.citation: J Clin Invest. 2001 Jun;107(12):1507-8
references.pmid: 11413157