This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mukherjee, S. Articles by Tanowitz, H. B. Search for Related Content PubMed PubMed Citation Articles by Mukherjee, S. Articles by Tanowitz, H. B.

 Previous Article  |  Next Article 

Infection and Immunity, September 2004, p. 5274-5282, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5274-5282.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Trypanosoma cruzi Infection Activates Extracellular Signal-Regulated Kinase in Cultured Endothelial and Smooth Muscle Cells

Shankar Mukherjee,¹ Huan Huang,¹ Stefka B. Petkova,² Chris Albanese,³ Richard G. Pestell,³ Vicki L. Braunstein,¹ George J. Christ,^4,5 Murray Wittner,¹ Michael P. Lisanti,⁶ Joan W. Berman,^1,7 Louis M. Weiss,^1,8 and Herbert B. Tanowitz^1,8*

Departments of Pathology,¹ Urology,⁴ Physiology and Biophysics,⁵ Molecular Pharmacology,⁶ Microbiology and Immunology,⁷ Medicine, Albert Einstein College of Medicine, Bronx, New York,⁸ Department of Biochemistry and the Lombardi Cancer Center, Georgetown University, Washington, D.C.,³ Jackson Laboratories, Bar Harbor, Maine²

Received 29 March 2004/ Returned for modification 3 May 2004/ Accepted 11 June 2004

Trypanosoma cruzi infection causes cardiomyopathy and vasculopathy. We examined the consequence of this infection for the mitogen-activated protein kinase (MAPK) pathways, which regulate cell proliferation in cultured human umbilical vein endothelial and vascular smooth muscle cells. Infection of these cells resulted in activation of extracellular signal-regulated kinases 1and 2 (ERK1/2) but not c-Jun N-terminal kinase or p38 MAPK. Treatment of these cells with the MAPK kinase inhibitor PD98059 prior to infection blocked the increase in phosphorylated ERK1/2 seen with infection. Heat-killed parasites did not activate ERK1/2, indicating that activation of ERK1/2 was dependent on infection of these cells by live parasites. Furthermore, transfection with dominant-negative Raf(301) or Ras(N17) constructs reduced the infection-associated levels of phospho-ERK1/2, indicating that the activation of ERK1/2 involved the Ras-Raf-ERK pathway. Infection also resulted in an increase in activator protein 1 (AP-1) activity, which was inhibited by transfection with a dominant-negative Raf(301) construct. T. cruzi-infected endothelial cells secreted endothelin-1 and interleukin-1ß, which activated ERK1/2 and induced cyclin D1 expression in uninfected smooth muscle cells. These data suggest a possible molecular paradigm for the pathogenesis of the vasculopathy and the cardiovascular remodeling associated with T. cruzi infection.

---

* Corresponding author. Mailing address: Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-3342. Fax: (718) 430-8543. E-mail: tanowitz{at}aecom.yu.edu.

Editor: W. A. Petri, Jr.

---

Infection and Immunity, September 2004, p. 5274-5282, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5274-5282.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Ashton, A. W., Mukherjee, S., Nagajyothi, F., Huang, H., Braunstein, V. L., Desruisseaux, M. S., Factor, S. M., Lopez, L., Berman, J. W., Wittner, M., Scherer, P. E., Capra, V., Coffman, T. M., Serhan, C. N., Gotlinger, K., Wu, K. K., Weiss, L. M., Tanowitz, H. B. (2007). Thromboxane A2 is a key regulator of pathogenesis during Trypanosoma cruzi infection. JEM 204: 929-940 [Abstract] [Full Text]  
• Hassan, G. S., Mukherjee, S., Nagajyothi, F., Weiss, L. M., Petkova, S. B., de Almeida, C. J., Huang, H., Desruisseaux, M. S., Bouzahzah, B., Pestell, R. G., Albanese, C., Christ, G. J., Lisanti, M. P., Tanowitz, H. B. (2006). Trypanosoma cruzi Infection Induces Proliferation of Vascular Smooth Muscle Cells. Infect. Immun. 74: 152-159 [Abstract] [Full Text]  
• Tanowitz, H. B., Huang, H., Jelicks, L. A., Chandra, M., Loredo, M. L., Weiss, L. M., Factor, S. M., Shtutin, V., Mukherjee, S., Kitsis, R. N., Christ, G. J., Wittner, M., Shirani, J., Kisanuki, Y. Y., Yanagisawa, M. (2005). Role of Endothelin 1 in the Pathogenesis of Chronic Chagasic Heart Disease. Infect. Immun. 73: 2496-2503 [Abstract] [Full Text]