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Gamma interferon/interleukin 10 balance in tissue lymphocytes correlates with down modulation of mucosal feline immunodeficiency virus infection.

ABSTRACT: Understanding the early cytokine response to lentiviral infections may be critical to the design of prevention and treatment strategies. By using the feline immunodeficiency virus (FIV) model, we have documented an interleukin 10 (IL10)-dominated response in lymphoid tissue CD4(+) and CD8(+) T lymphocytes within the first 4 weeks after mucosal FIV infection. This profile coincided with the period of high tissue viral replication. By 10 weeks postinfection, tissue viral levels decreased significantly, and gamma interferon (IFN gamma) production in CD8(+) T cells had increased to restore the IL10/IFN gamma ratio to control levels. Concurrently, increased production of IL6 and viral RNA was detected in macrophages. These temporal associations of viral replication with cytokine balance in tissues suggest roles for IL10 in the permissive stage of infection and IFN gamma in the subsequent down modulation of lentiviral infection.

SUBMITTER: Avery PR

PROVIDER: S-EPMC374259 | biostudies-literature | 2004 Apr

REPOSITORIES: biostudies-literature

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Gamma interferon/interleukin 10 balance in tissue lymphocytes correlates with down modulation of mucosal feline immunodeficiency virus infection.

Avery Paul R PR Hoover Edward A EA

Journal of virology 20040401 8

Understanding the early cytokine response to lentiviral infections may be critical to the design of prevention and treatment strategies. By using the feline immunodeficiency virus (FIV) model, we have documented an interleukin 10 (IL10)-dominated response in lymphoid tissue CD4(+) and CD8(+) T lymphocytes within the first 4 weeks after mucosal FIV infection. This profile coincided with the period of high tissue viral replication. By 10 weeks postinfection, tissue viral levels decreased significa ...[more]

PMID: 15047817

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Project description:UnlabelledInterleukin-10 (IL-10) is an immunomodulatory cytokine that is important for maintenance of epithelial cell (EC) survival and anti-inflammatory responses (AIR). The majority of HIV infections occur through the mucosal route despite mucosal epithelium acting as a barrier to human immunodeficiency virus (HIV). Therefore, understanding the role of IL-10 in maintenance of intestinal homeostasis during HIV infection is of interest for better characterization of the pathogenesis of HIV-mediated enteropathy. We demonstrated here changes in mucosal IL-10 signaling during simian immunodeficiency virus (SIV) infection in rhesus macaques. Disruption of the epithelial barrier was manifested by EC apoptosis and loss of the tight-junction protein ZO-1. Multiple cell types, including a limited number of ECs, produced IL-10. SIV infection resulted in increased levels of IL-10; however, this was associated with increased production of mucosal gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α), suggesting that IL-10 was not able to regulate AIR. This observation was supported by the downregulation of STAT3, which is necessary to inhibit production of IFN-γ and TNF-α, and the upregulation of SOCS1 and SOCS3, which are important regulatory molecules in the IL-10-mediated AIR. We also observed internalization of the IL-10 receptor (IL-10R) in mucosal lymphocytes, which could limit cellular availability of IL-10 for signaling and contribute to the loss of a functional AIR. Collectively, these findings demonstrate that internalization of IL-10R with the resultant impact on IL-10 signaling and dysregulation of the IL-10-mediated AIR might play a crucial role in EC damage and subsequent SIV/HIV pathogenesis.ImportanceInterleukin-10 (IL-10), an important immunomodulatory cytokine plays a key role to control inflammatory function and homeostasis of the gastrointestinal mucosal immune system. Despite recent advancements in the study of IL-10 and its role in HIV infection, the role of mucosal IL-10 in SIV/HIV infection in inducing enteropathy is not well understood. We demonstrated changes in mucosal IL-10 signaling during SIV infection in rhesus macaques. Disruption of the intestinal epithelial barrier was evident along with the increased levels of mucosal IL-10 production. Increased production of mucosal IFN-γ and TNF-α during SIV infection suggested that the increased level of mucosal IL-10 was not able to regulate anti-inflammatory responses. Our findings demonstrate that internalization of IL-10R with the resultant impact on IL-10 signaling and dysregulation of the IL-10-mediated anti-inflammatory responses might play a crucial role in epithelial cell damage and subsequent SIV/HIV pathogenesis.

Dataset Information

Gamma interferon/interleukin 10 balance in tissue lymphocytes correlates with down modulation of mucosal feline immunodeficiency virus infection.

Publications

Gamma interferon/interleukin 10 balance in tissue lymphocytes correlates with down modulation of mucosal feline immunodeficiency virus infection.

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