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Infection and Immunity, May 2003, p. 2859-2867, Vol. 71, No. 5
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.5.2859-2867.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Activation of Transcription Factors AP-1 and NF-B in Murine Chagasic Myocarditis

Huan Huang,¹ Stefka B. Petkova,^1, Alex W. Cohen,² Boumediene Bouzahzah,³ John Chan,^4,5 Jian-nian Zhou,³ Stephen M. Factor,^1,4 Louis M. Weiss,^1,4 Mohan Krishnamachary,¹ Shankar Mukherjee,¹ Murray Wittner,¹ Richard N. Kitsis,^4,6 Richard G. Pestell,^3,4, Michael P. Lisanti,² Chris Albanese,^3, and Herbert B. Tanowitz^1,4*

Departments of Pathology,¹ Molecular Pharmacology,² Developmental and Molecular Biology,³ Medicine,⁴ Microbiology and Immunology,⁵ Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461⁶

Received 9 December 2002/ Returned for modification 24 January 2003/ Accepted 6 February 2003

The myocardium of CD1 mice was examined for the activation of signal transduction pathways leading to cardiac inflammation and subsequent remodeling during Trypanosoma cruzi infection (Brazil strain). The activity of three pathways of the mitogen-activated protein kinases (MAPKs) was determined. Immunoblotting revealed a persistent elevation of phosphorylated (activated) extracellular-signal-regulated kinase (ERK), which regulates cell proliferation. During infection there was a transient activation of p38 MAPK but no activation of Jun N-terminal kinase. Early targets of activated ERK, c-Jun and c-Fos, were elevated during infection, as demonstrated by semiquantitative reverse transcription-PCR. Immunostaining revealed that the endothelium and the interstitial cells were most intensely stained with antibodies to c-Jun and c-Fos. Soon after infection, AP-1 and NF-B DNA binding activity was increased. Protein levels of cyclin D1, the downstream target of ERK and NF-B, were induced during acute infection. Immunostaining demonstrated increased expression of cyclin D1 in the vascular and endocardial endothelium, inflammatory cells, and the interstitial areas. Increased expression of the cyclin D1-specific phosphorylated retinoblastoma protein (Ser780) was also evident. Immunoblotting and immunostaining also demonstrated increased expression of proliferating cellular nuclear antigen that was predominantly present in the inflammatory cells, interstitial areas (i.e., fibroblasts), and endothelium. These data demonstrate that T. cruzi infection results in activation of the ERK-AP-1 pathway and NF-B. Cyclin D1 expression was also increased. These observations provide a molecular basis for the activation of pathways involved in cardiac remodeling in chagasic cardiomyopathy.

Editor: W. A. Petri, Jr.

Present address: The Jackson Laboratories, Bar Harbor, Maine.

Present address: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057.

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