A human IL10 BAC transgene reveals tissue-specific control of IL-10 expression and alters disease outcome

Dilini Ranatunga, Christian M. Hedrich, Wang Fengying, Daniel W. McVicar, Nathan Nowak, Trupti Joshi, Lionel Feigenbaum, Lindsay R. Grant, Simona Stäger, Jay H. Bream

Research output: Contribution to journalArticlepeer-review

Abstract

Interleukin (IL)-10 is an immunoregulatory cytokine that is produced by diverse cell populations. Studies in mice suggest that the cellular source of IL-10 is a key determinant in various disease pathologies, yet little is known regarding the control of tissue-specific human IL-10 expression. To assess cell type-specific human IL-10 regulation, we created a human IL-10 transgenic mouse with a bacterial artificial chromosome (hIL10BAC) in which the IL10 gene is positioned centrally. Since human IL-10 is biologically active in the mouse, we could examine the in vivo capacity of tissue-specific human IL-10 expression to recapitulate IL-10-dependent phenotypes by reconstituting Il10-/- mice (Il10-/-/hIL10BAC). In response to LPS, Il10-/-/ hIL10BAC mice proficiently regulate IL-10-target genes and normalize sensitivity to LPS toxicity via faithful human IL-10 expression from macrophages and dendritic cells. However, in the Leishmania donovani model of pathogen persistence, Il10-/-/hIL10BAC mice did not develop the characteristic IL-10+IFN-γ+CD4 T cell subset thought to mediate persistence and, like Il10-/- mice, cleared the parasites. Furthermore, the IL-10-promoting cytokine IL-27 failed to regulate transgenic human IL-10 production in CD4+ T cells in vitro which together suggests that the hIL10BAC encodes for weak T cell-specific IL-10 expression. Thus, the hIL10BAC mouse is a model of human gene structure and function revealing tissue-specific regulatory requirements for IL-10 expression which impacts disease outcomes.

Original languageEnglish (US)
Pages (from-to)17123-17128
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number40
DOIs
StatePublished - Oct 6 2009

Keywords

  • IL-27
  • LPS
  • Leishmania
  • T cell
  • Transgenic

ASJC Scopus subject areas

  • General

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