SEARCH:   Advanced

Blood, 1 May 2008, Vol. 111, No. 9, pp. 4424. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Malinin, N. Articles by Byzova, T. Search for Related Content PubMed PubMed Citation Articles by Malinin, N. Articles by Byzova, T. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Donners et al, page 4596 CD40/TRAF6 switch in neointimal hyperplasia Nikolay Malinin, and Tatiana Byzova CLEVELAND CLINIC FOUNDATION An article by Donner and colleagues in this issue of Blood describes a specific role for the CD40L/CD40/TRAF6 signaling axis in neointima formation upon carotid injury. In this model, several key parameters of neointimal remodeling are demonstrated to be dependent on CD40 signaling through the TRAF6 binding site, but not the TRAF2,3,5 binding site. CD40 receptor is a member of the TNF receptor family with a prominent role in the regulation of adaptive immune response. The receptor's stimulation by specific CD40 ligand (CD40L) results in activation of macrophages, B cells, and dendritic cells. Vascular cells also express CD40, and stimulation by CD40L mediates inflammatory responses in the vascular wall. The 2 major signaling mediators downstream of CD40 are TRAF2 and TRAF6. Whereas TRAF2 function seems to be confined to the signaling of the TNF receptor family, TRAF6 seems to function more broadly as a mediator of IL-1 and Toll-like receptor signaling.1 TRAF2 and TRAF6 have distinct binding sites in the CD40 intracellular domain, structurally different from each other. CD40/CD40L signaling appears to underlie a number of cardiovascular pathologies, and elevated levels of soluble CD40L have been shown to predict cardiovascular events. Previously published analyses of animal models have demonstrated opposing effects of CD40L knock-out (KO) on arteriosclerosis2 and acute collar-induced arterial injury.3 The study by Donner et al shows that, upon carotid ligation, neointima formation is substantially reduced in CD40 KO, which is attributed to bone marrow–dependent functions. Indeed, the study documents defective infiltration of CD40-null leukocytes to endothelium, which might result in reduced infiltration of inflammatory cells into the vessel wall. Analysis of the neointima of CD40–/– animals showed dramatic reduction in CD45-positive cells. Similar reduction is observed in animals expressing CD40 receptor with impaired TRAF6 binding site (CD40-T6), but not TRAF2 binding site (CD40-T2). These analyses conclusively demonstrate that CD40/TRAF6 regulates infiltration of pro-inflammatory cells into the vessel wall and, consequently, neointima formation. Intriguingly, the effect of CD40L KO was minimal compared with CD40 KO, suggesting the possibility of an alternative CD40 ligand. CD40L interaction with IIb/β3 integrins in thrombosis4 also complicates analysis while suggesting that the phenotypes of CD40L and CD40-null mice are not completely identical. The intriguing novelty of the study by Donner and colleagues lies in its demonstration of a functional dichotomy downstream of CD40. In CD40L and CD40 KO animals, as well as in the case of CD40-T6 mutants, carotid ligation leads to reduced leukocytes infiltration, vessel restructuring, and metalloprotease activity. However, CD40 mutation with an impaired TRAF2,3,5 binding site (CD40-T2) has no such effect. Either TRAF6 or the TRAF2,3,5 binding site is sufficient for CD40L-triggered NF-B and JNK stimulation. Nevertheless, knockout of TRAF6 expression rendered cells CD40L-unresponsive. The explanation for this phenomenon is the formation of TRAF2/TRAF6 heterodimers compensating for the mutation in the TRAF6 binding site. However, IL-6 induction has been reported as fully dependent on the TRAF6 binding site (reviewed in Hostager1), similar to the effect on neointima formation, while CD80 up-regulation is induced when either of the 2 binding sites is present. The molecular mechanism of CD40/TRAF6 signaling awaits further exploration. Importantly, careful analysis of the CD40/TRAF6 axis might result in the development of novel therapeutic strategies designed to block only selected CD40 functions without affecting the others. Footnotes Conflict-of-interest disclosure: The authors declare no competing financial interests. REFERENCES Hostager BS. Roles of TRAF6 in CD40 signaling. Immunol Res. 2007;39:105–114.[CrossRef][Medline] [Order article via Infotrieve] Hancock WW, Buelow R, Sayegh MH, Turka LA. Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes. Nat Med. 1998;4:1392–1396.[CrossRef][Medline] [Order article via Infotrieve] Remskar M, Li H, Chyu K-Y, Shah PK, Cercek B. Absence of CD40 signaling is associated with an increase in intimal thickening after arterial injury. Circ Res. 2001;88:390–394.[Abstract/Free Full Text] Andre P, Prasad KSS, Denis CV, et al. CD40L stabilizes arterial thrombi by a b3 integrin-dependent mechanism. Nat Med. 2002;8:247–252.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling Marjo M. P. C. Donners, Linda Beckers, Dirk Lievens, Imke Munnix, Johan Heemskerk, Ben J. Janssen, Erwin Wijnands, Jack Cleutjens, Alma Zernecke, Christian Weber, Cory L. Ahonen, Ulrike Benbow, Andrew C. Newby, Randolph J. Noelle, Mat J. A. P. Daemen, and Esther Lutgens Blood 2008 111: 4596-4604. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Malinin, N. Articles by Byzova, T. Search for Related Content PubMed PubMed Citation Articles by Malinin, N. Articles by Byzova, T. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020