title: Lack of interleukin-10-mediated anti-inflammatory signals and upregulated interferon gamma production are linked to increased intestinal epithelial cell apoptosis in pathogenic simian immunodeficiency virus infection.
abstract: Interleukin-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.
  
  
  OBJECTIVE
  Interleukin-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.
authors.affiliation: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Diganta
authors.initials: D
authors.lastname: Pan
authors.affiliation: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Carys S
authors.initials: CS
authors.lastname: Kenway-Lynch
authors.affiliation: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Lala
authors.affiliation: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA Tulane University School of Medicine, New Orleans, Louisiana, USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Veazey
authors.affiliation: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA Tulane University School of Medicine, New Orleans, Louisiana, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lackner
authors.affiliation: Division of Microbiology, Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Arpita
authors.initials: A
authors.lastname: Das
authors.affiliation: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA Tulane University School of Medicine, New Orleans, Louisiana, USA bpahar@tulane.edu.
authors.forename: Bapi
authors.initials: B
authors.lastname: Pahar
mesh_terms: D000818:Animals; D017209:Apoptosis; D004847:Epithelial Cells / Q000502:physiology* / Q000821:virology; D005260:Female; D007371:Interferon-gamma / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology / Q000821:virology; D008253:Macaca mulatta; D008297:Male; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma