| First Author | Ranatunga D | Year | 2009 |
| Journal | Proc Natl Acad Sci U S A | Volume | 106 |
| Issue | 40 | Pages | 17123-8 |
| PubMed ID | 19805095 | Mgi Jnum | J:153695 |
| Mgi Id | MGI:4366117 | Doi | 10.1073/pnas.0904955106 |
| Citation | Ranatunga D, et al. (2009) A human IL10 BAC transgene reveals tissue-specific control of IL-10 expression and alters disease outcome. Proc Natl Acad Sci U S A 106(40):17123-8 |
| abstractText | 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. |
