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

  1. Author:
    Ranatunga, D.
    Hedrich, C. M.
    Wang, F. Y.
    McVicar, D. W.
    Nowak, N.
    Joshi, T.
    Feigenbaum, L.
    Grant, L. R.
    Stager, S.
    Bream, J. H.

  2. Author Address

    Ranatunga, Dilini, Hedrich, Christian M.; Wang, Fengying, Grant, Lindsay R.; Bream, Jay H.] Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [McVicar, Daniel W.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. [Nowak, Nathan] Transnetyx Inc, Cordova, TN 38016 USA. [Joshi, Trupti, Staeger, Simona] Johns Hopkins Sch Med, Baltimore, MD 21205 USA. [Feigenbaum, Lionel] NCI, SAIC Frederick, Frederick, MD 21702 USA.
    1. Year: 2009
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 106
    2. 40
    3. Pages: 17123-17128
  4. Type of Article: Article
  1. 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-gamma(+)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.

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  2. DOI: 10.1073/pnas.0904955106
  3. PMID: 19805095

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