Sophie Lanone, Tao Zheng, Zhou Zhu, Wei Liu, Chun Geun Lee, Bing Ma, Qingsheng Chen, Robert J. Homer, Jingming Wang, Lesley A. Rabach, Morgan E. Rabach, J. Michael Shipley, Steven D. Shapiro, Robert M. Senior, Jack A. Elias
David M. Koelle, Zhi Liu, Christopher M. McClurkan, Max S. Topp, Stanley R. Riddell, Eric G. Pamer, Andrew S. Johnson, Anna Wald, Lawrence Corey
Kaoru Saegusa, Naozumi Ishimaru, Kumiko Yanagi, Rieko Arakaki, Kouichi Ogawa, Ichiro Saito, Nobuhiko Katunuma, Yoshio Hayashi
Thais P. Salazar-Mather, Casey A. Lewis, Christine A. Biron
Michael J. Walter, Jeffrey D. Morton, Naohiro Kajiwara, Eugene Agapov, Michael J. Holtzman
Terry Davies, Russell Marians, Rauf Latif
Tania Nikolcheva, Stephane Pyronnet, Szu-yi Chou, Nahum Sonenberg, An Song, Carol Clayberger, Alan M. Krensky
Niels C. Riedemann, Ren-Feng Guo, Thomas A. Neff, Ines J. Laudes, Katie A. Keller, Vidya J. Sarma, Maciej M. Markiewski, Dimitrios Mastellos, Christoph W. Strey, Carl L. Pierson, John D. Lambris, Firas S. Zetoune, Peter A. Ward
Group B coxsackieviral (CVB) infection commonly causes viral myocarditis. Mice are protected from CVB3 myocarditis by gene-targeted knockout of p56Lck(Lck), the Src family kinase (Src) essential for T cell activation. Extracellular signal-regulated kinase 1 and 2 (ERK-1/2) can influence cell function downstream of Lck. Using T cell lines and neonatal cardiac myocytes we investigated the role of ERK-1/2 in CVB3 infection. In Jurkat T cells ERK-1/2 is rapidly activated by CVB3; but, this response is absent in Lck-negative JCaM T cells. Inhibition of ERK-1/2 with UO126 reduced CVB3 titers in Jurkat cells, but not in JCaM cells. In cardiac myocytes CVB3 activation of ERK-1/2 is blocked by the Src inhibitor PP2. In addition, viral production in myocytes is decreased by Src or ERK-1/2 inhibition. In vitro, in both immune and myocardial cells, ERK-1/2 is activated by CVB3 downstream of Lck and other Src’s and is necessary for efficient CVB3 replication. In vivo, following CVB3 infection, ERK-1/2 activation is evident in the myocardium. ERK-1/2 activation is intense in the hearts of myocarditis-susceptible A/J mice. In contrast, significantly less ERK-1/2 activation is found in the hearts of myocarditis-resistant C57BL/6 mice. Therefore, the ERK-1/2 response to CVB3 infection may contribute to differential host susceptibility to viral myocarditis.
Mary Anne Opavsky, Tami Martino, Marlene Rabinovitch, Josef Penninger, Chris Richardson, Martin Petric, Cathy Trinidad, Lisa Butcher, Janice Chan, Peter P. Liu
Estrogen is thought to contribute to the increased frequency of autoimmune disorders occurring in females, but a molecular basis for its effects on autoimmunity remains to be elucidated. We have shown previously that estrogen leads to the survival and activation of autoreactive cells in the naive repertoire. To identify the molecular pathways involved in B cell tolerance, we sought to identify genes that are differentially regulated by estrogen in mouse B cells. Several genes involved in B cell activation and survival, including cd22, shp-1, bcl-2, and vcam-1, were upregulated by estrogen in B cells. We found that overexpression of CD22 and SHP-1 in B cells decreased B cell receptor signaling. Estrogen receptors α and β are expressed on B cells and are functional, since they can directly upregulate expression of CD22, SHP-1, and Bcl-2. Estrogen treatment protected isolated primary B cells from B cell receptor–mediated apoptosis. These results suggest that estrogen induces a genetic program that alters survival and activation of B cells in a B cell–autonomous fashion and thus skews the naive immune system toward autoreactivity.
Christine M. Grimaldi, James Cleary, A. Selma Dagtas, Dariush Moussai, Betty Diamond