TY - JOUR
T1 - A human IL10 BAC transgene reveals tissue-specific control of IL-10 expression and alters disease outcome
AU - Ranatunga, Dilini
AU - Hedrich, Christian M.
AU - Fengying, Wang
AU - McVicar, Daniel W.
AU - Nowak, Nathan
AU - Joshi, Trupti
AU - Feigenbaum, Lionel
AU - Grant, Lindsay Renee
AU - Stäger, Simona
AU - Bream, Jay H.
PY - 2009/10/6
Y1 - 2009/10/6
N2 - 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.
AB - 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.
KW - IL-27
KW - LPS
KW - Leishmania
KW - T cell
KW - Transgenic
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U2 - 10.1073/pnas.0904955106
DO - 10.1073/pnas.0904955106
M3 - Article
C2 - 19805095
AN - SCOPUS:70350133985
VL - 106
SP - 17123
EP - 17128
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 40
ER -