Regulation of endothelial cell adhesion molecule expression by mast cells, macrophages, and neutrophils.
BACKGROUND
Leukocyte adhesion to the vascular endothelium and subsequent transendothelial migration play essential roles in the pathogenesis of cardiovascular diseases such as atherosclerosis. The leukocyte adhesion is mediated by localized activation of the endothelium through the action of inflammatory cytokines. The exact proinflammatory factors, however, that activate the endothelium and their cellular sources remain incompletely defined.


RESULTS
Using bone marrow-derived mast cells from wild-type, Tnf(-/-), Ifng(-/-), Il6(-/-) mice, we demonstrated that all three of these pro-inflammatory cytokines from mast cells induced the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin in murine heart endothelial cells (MHEC) at both mRNA and protein levels. Compared with TNF-α and IL6, IFN-γ appeared weaker in the induction of the mRNA levels, but at protein levels, both IL6 and IFN-γ were weaker inducers than TNF-α. Under physiological shear flow conditions, mast cell-derived TNF-α and IL6 were more potent than IFN-γ in activating MHEC and in promoting neutrophil adhesion. Similar observations were made when neutrophils or macrophages were used. Neutrophils and macrophages produced the same sets of pro-inflammatory cytokines as did mast cells to induce MHEC adhesion molecule expression, with the exception that macrophage-derived IFN-γ showed negligible effect in inducing VCAM-1 expression in MHEC.


CONCLUSIONS
Mast cells, neutrophils, and macrophages release pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL6 that induce expression of adhesion molecules in endothelium and recruit of leukocytes, which is essential to the pathogenesis of vascular inflammatory diseases.
Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
Jie
J
Zhang
Pilar
P
Alcaide
Li
L
Liu
Jiusong
J
Sun
Aina
A
He
Francis W
FW
Luscinskas
Guo-Ping
GP
Shi
D000818:Animals; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000235:genetics*; D002634:Chemotaxis, Leukocyte; D016207:Cytokines; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology*; D007249:Inflammation / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000502:physiology*; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D009504:Neutrophils / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis
D015815:Cell Adhesion Molecules; D016207:Cytokines; D012333:RNA, Messenger
Arterioscler Thromb Vasc Biol. 2008 Jan;28(1):84-9
17991873
Arterioscler Thromb Vasc Biol. 1997 Aug;17(8):1517-20
9301629
J Clin Invest. 2007 Nov;117(11):3359-68
17932568
Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7390-7
7519775
Heart. 2008 Aug;94(8):1002-7
18308864
Proc Natl Acad Sci U S A. 1987 Dec;84(24):9238-42
2827173
J Immunol. 1986 Jul 1;137(1):245-54
3086451
Med Electron Microsc. 2002 Dec;35(4):179-203
12658354
Circulation. 2000 Oct 24;102(17):2118-23
11044430
J Clin Invest. 2001 May;107(10):1255-62
11375415
Microcirculation. 2000 Jun;7(3):201-14
10901499
J Exp Med. 2000 Jan 3;191(1):189-94
10620617
Am J Pathol. 2003 May;162(5):1591-601
12707043
J Allergy Clin Immunol. 1998 Sep;102(3):461-8
9768589
Circ Res. 2008 Feb 1;102(2):209-17
17991882
Am J Pathol. 1992 Mar;140(3):665-73
1372160
Nat Rev Immunol. 2008 Oct;8(10):802-15
18825131
Am J Pathol. 2003 Dec;163(6):2413-20
14633613
Am J Cardiol. 1997 Mar 15;79(6):742-7
9070552
J Immunol. 1992 Dec 15;149(12):4021-8
1460288
J Cell Physiol. 1995 Oct;165(1):40-53
7559805
Immunol Cell Biol. 2002 Apr;80(2):170-7
11940118
Am J Pathol. 1994 May;144(5):952-61
7513951
Circulation. 2002 Dec 3;106(23):2894-900
12460868
Circ Res. 1998 May 4;82(8):871-8
9580553
Blood. 2009 Aug 20;114(8):1696-706
19546478
Nat Med. 2009 Aug;15(8):940-5
19633655
Physiol Rev. 1999 Jan;79(1):181-213
9922371
Atherosclerosis. 2009 Jan;202(1):111-8
18508059
Hum Pathol. 1985 Jun;16(6):562-8
3997134
Science. 1991 Feb 15;251(4995):788-91
1990440
Am J Pathol. 2010 Jul;177(1):493-500
20472897
J Pathol. 1993 Nov;171(3):223-9
7506307
Circ Res. 1999 Jun 11;84(11):1237-44
10364560
Nat Med. 2007 Jun;13(6):719-24
17546038
J Cell Biol. 1995 Feb;128(4):661-71
7532174
Circulation. 2000 May 16;101(19):2290-5
10811597