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Published online before print November 30, 2007
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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070017

Accepted for publication September 11, 2007.

Article

Gastrointestinal Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques Is Characterized by Proinflammatory Dysregulation of the Interleukin-6-Janus Kinase/Signal Transducer and Activator of Transcription3 Pathway

Mahesh Mohan, Pyone P. Aye, Juan T. Borda, Xavier Alvarez, and Andrew A. Lackner@

From the Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana

@ To whom correspondence should be addressed. E-mail: alackner{at}tulane.edu.


  Abstract

Gastrointestinal disease and inflammation are common sequelae of human and simian immunodeficiency virus (SIV) infection. Nevertheless, the molecular mechanisms that lead to gastrointestinal dysfunction remain unclear. We investigated regulation of the interleukin (IL)-6-JAK-STAT3 pathway in jejunum and colon, collected at necropsy, from 10 SIV-infected macaques with diarrhea (group 1), 10 non-SIV-infected macaques with diarrhea (group 2), and 7 control uninfected macaques (group 3). All group 1 and 2 macaques had chronic diarrhea, wasting, and colitis, but group 1 animals had more frequent and severe lesions in the jejunum. A significant increase in IL-6 and SOCS-3 gene expression along with constitutive STAT3 activation was observed in the colon of all group 1 and 2 macaques and in the jejunum of only group 1 macaques compared to controls. Further, in colon, histopathology severity scores correlated significantly with IL-6 (groups 1 and 2) and SOCS-3 (group 2) gene expression. In jejunum, a similar correlation was observed only in group 1 animals. Phosphorylated STAT3 (p-STAT3) was localized to lymphocytes (CD3+) and macrophages (CD68+), with fewer CD3+ lymphocytes expressing p-STAT3 in group 1 macaques. Despite high SOCS-3 expression, STAT3 remained constitutively active, providing a possible explanation for persistent intestinal inflammation and immune activation that may favor viral replication and disease pro-gression.




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M. Mohan, P. P. Aye, J. T. Borda, X. Alvarez, and A. A. Lackner
CCAAT/Enhancer Binding Protein {beta} Is a Major Mediator of Inflammation and Viral Replication in the Gastrointestinal Tract of Simian Immunodeficiency Virus-Infected Rhesus Macaques
Am. J. Pathol., July 1, 2008; 173(1): 106 - 118.
[Abstract] [Full Text] [PDF]


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Copyright © 2007 by the American Society for Investigative Pathology.