Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 171, Issue 6, Pages 1952-1965Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2007.070017
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Funding
- NCRR NIH HHS [RR19607, RR00164, P51 RR000164, G20 RR019607] Funding Source: Medline
- NIAID NIH HHS [R01 AI065325, AI065325] Funding Source: Medline
- NIDDK NIH HHS [R01 DK050550, DK50550] Funding Source: Medline
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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 I 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 I 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 I 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 I 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 progression.
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