Thy-1-integrin alphav beta5 interactions inhibit lung fibroblast contraction-induced latent transforming growth factor-beta1 activation and myofibroblast differentiation.
Myofibroblasts, key effector cells in tissue fibrosis, are specialized contractile cells. Lung myofibroblast contraction induces integrin alpha(v)beta(5)-dependent latent transforming growth factor (TGF)-beta1 activation suggests that myofibroblast contractility may be a driving force for the persistent myofibroblast differentiation observed in fibrotic lungs. Understanding the mechanisms that regulate fibroblast contraction and mechanotransduction will add new insights into the pathogenesis of lung fibrosis and may lead to new therapeutic approaches for treating fibrotic lung diseases. We and others previously demonstrated that lung fibroblast expression of Thy-1 prevents lung fibrosis. The mechanisms underlying the anti-fibrotic effect of Thy-1 are not well understood. In this study, we showed that Thy-1 interacts with integrin alpha(v)beta(5), both in a cell-free system and on the cell surface of rat lung fibroblasts. Thy-1-integrin alpha(v)beta(5) interactions are RLD-dependent because mutated Thy-1, in which RLD is replaced by RLE, loses the ability to bind the integrin. Furthermore, Thy-1 expression prevents fibroblast contraction-induced, integrin alpha(v)beta(5)-dependent latent TGF-beta1 activation and TGF-beta1-dependent lung myofibroblast differentiation. In contrast, lack of Thy-1 expression or disruption of Thy-1-alpha(v)beta(5) interactions renders lung fibroblasts susceptible to contraction-induced latent TGF-beta1 activation and myofibroblast differentiation. These data suggest that Thy-1-integrin alpha(v)beta(5) interactions inhibit contraction-induced latent TGF-beta1 activation, presumably by blocking the binding of extracellular matrix-bound latent TGF-beta1 with integrin alpha(v)beta(5). Our studies suggest that targeting key mechanotransducers to inhibit mechanotransduction might be an effective approach to inhibit the deleterious effects of myofibroblast contraction on lung fibrogenesis.
Zhou
Yong
Y
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. yzhou@uab.edu
Hagood
James S
JS
Lu
Baogen
B
Merryman
W David
WD
Murphy-Ullrich
Joanne E
JE
D020816:Amino Acid Motifs; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002474:Cell-Free System; D019332:Endothelin-1 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D055767:Immobilized Proteins / Q000378:metabolism; D008168:Lung / Q000166:cytology*; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D032446:Myoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D019030:Receptors, Vitronectin / Q000378:metabolism*; D012995:Solubility / Q000187:drug effects; D018800:Thy-1 Antigens / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D019332:Endothelin-1; D055767:Immobilized Proteins; D010080:Oxazoles; D019030:Receptors, Vitronectin; D018800:Thy-1 Antigens; D053773:Transforming Growth Factor beta1; C064660:integrin alphaVbeta5
Biol Res. 2002;35(2):231-8
12415741
J Cell Biol. 1999 Nov 29;147(5):1023-38
10579722
Curr Rheumatol Rep. 2009 Apr;11(2):120-6
19296884
J Cell Biol. 2004 Jun 7;165(5):723-34
15184403
Biochem J. 2002 Oct 15;367(Pt 2):517-24
12144526
J Cell Physiol. 1984 Oct;121(1):184-8
6090474
Eur Respir J. 1994 Dec;7(12):2131-8
7536165
Exp Cell Res. 2006 Nov 15;312(19):3752-67
17027000
Crit Rev Clin Lab Sci. 2004;41(3):233-64
15307633
J Biol Chem. 2005 Mar 4;280(9):7409-12
15611103
Annu Rev Cell Dev Biol. 1996;12:697-715
8970741
Curr Biol. 2001 Jul 10;11(13):1028-38
11470407
Am J Respir Crit Care Med. 2001 Sep 15;164(6):1025-32
11587991
Science. 1980 Apr 11;208(4440):177-9
6987736
Mol Biol Cell. 2001 Sep;12(9):2730-41
11553712
Am J Physiol Lung Cell Mol Physiol. 2003 Aug;285(2):L415-26
12740219
Am J Respir Cell Mol Biol. 2007 Feb;36(2):226-35
16960126
Am J Pathol. 2004 Aug;165(2):659-69
15277239
Exp Cell Res. 1999 May 1;248(2):608-19
10222153
Am J Pathol. 2005 Aug;167(2):365-79
16049324
Science. 1996 Jul 12;273(5272):245-8
8662509
Am J Physiol Lung Cell Mol Physiol. 2007 Sep;293(3):L525-34
17631612
J Cell Biol. 2002 May 13;157(4):657-63
11994316
J Invest Dermatol. 1998 May;110(5):771-6
9579544
Annu Rev Physiol. 2006;68:345-74
16460276
Mol Cell Biol. 1988 Oct;8(10):4162-8
3185545
Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):59-69
10708953
Biochemistry. 1990 Jul 24;29(29):6851-7
2397217
J Cell Biol. 1994 Jan;124(1-2):171-81
8294500
J Cell Biol. 1995 Aug;130(4):887-95
7543902
J Cell Biol. 2004 Oct 11;167(1):123-33
15466481
Mol Biol Cell. 2004 Jul;15(7):3497-508
15133124
Am J Pathol. 2007 Jun;170(6):1807-16
17525249
Am J Pathol. 1999 Mar;154(3):871-82
10079265
J Biol Chem. 1992 Dec 15;267(35):25378-84
1281156
Biochim Biophys Acta. 2008 Jun;1783(6):1111-20
18346467
Biochem J. 2005 Dec 15;392(Pt 3):641-8
16201970
J Cell Biol. 1979 Apr;81(1):83-91
383722
PLoS One. 2009 Aug 12;4(8):e6608
19672301
J Cell Biol. 2007 Jan 29;176(3):355-67
17242066
Biochem Soc Trans. 2007 Aug;35(Pt 4):661-4
17635115
Am J Respir Cell Mol Biol. 2000 Oct;23(4):460-5
11017910
J Cell Biol. 2007 Dec 17;179(6):1311-23
18086923
Anal Biochem. 1994 Feb 1;216(2):276-84
8179182
EMBO Rep. 2010 Feb;11(2):97-105
20075988
J Invest Dermatol. 2006 Feb;126(2):441-52
16374458
J Invest Dermatol. 2006 Aug;126(8):1761-9
16675963
J Cell Biol. 1998 Apr 20;141(2):539-51
9548730
Nature. 1996 Jan 4;379(6560):91-6
8538749
Anal Biochem. 1994 May 15;219(1):144-6
8059941
J Biol Chem. 2002 Apr 26;277(17):14467-74
11839764
Biochem Soc Trans. 2009 Aug;37(Pt 4):849-54
19614606
Wound Repair Regen. 2006 May-Jun;14(3):313-20
16808810
Exp Cell Res. 2004 May 1;295(2):488-96
15093746
J Biol Chem. 2004 May 28;279(22):23510-6
15033989
Oncogene. 2005 Jul 7;24(29):4710-20
15897908
Wound Repair Regen. 2005 Jan-Feb;13(1):7-12
15659031
J Cell Biol. 2006 Jan 16;172(2):259-68
16401722
EMBO J. 1996 Jan 15;15(2):245-53
8617200
Exp Cell Res. 2000 Feb 1;254(2):210-20
10640419
Nat Rev Mol Cell Biol. 2002 May;3(5):349-63
11988769
Am J Pathol. 2009 Jan;174(1):21-33
19056849
Trends Cell Biol. 2004 Dec;14(12):657-9
15564041
J Histochem Cytochem. 1996 Aug;44(8):875-89
8756760
J Immunol. 2004 Mar 15;172(6):3850-9
15004192
J Biol Chem. 2005 May 13;280(19):18871-80
15677465
Chest. 2001 Jul;120(1 Suppl):64S-66S
11451929
J Clin Invest. 1995 Apr;95(4):1861-8
7706493
Cancer Metastasis Rev. 2005 Sep;24(3):395-402
16258727
Surgery. 2002 Mar;131(3):332-7
11894039