TY - JOUR
T1 - Stat4-dependent, T-bet-independent regulation of IL-10 in NK cells
AU - Grant, Lindsay Renee
AU - Yao, Z. J.
AU - Hedrich, C. M.
AU - Wang, F.
AU - Moorthy, A.
AU - Wilson, K.
AU - Ranatunga, D.
AU - Bream, J. H.
N1 - Funding Information:
We thank Dr John J O’Shea for his valuable support of this work. In addition, we thank the Johns Hopkins Becton Dickinson Immune Function Laboratory and Paul Fallon for assistance with flow cytometry-related experiments. We also thank Debbie Hodge and Howard Young for helpful discussions and critical review of this manuscript and for providing Tbet−/− and Ifng−/− mice. This work was supported by National Institutes of Health Grant AI070594 (to JHB).
PY - 2008/6
Y1 - 2008/6
N2 - Interleukin-10 (IL-10) is intensely studied, yet little is known about the mechanisms that control IL-10 expression. We identified striking similarities between IL-10 and interferon-γ (IFN-γ) regulation in mouse natural killer (NK) cells. Like IFN-γ, IL-10 expression is induced by IL-2 and IL-12 and IL-2+IL-12 stimulation is synergistic. Unlike IFN-γ, neither IL-18 nor Ly-49D cross-linking induced IL-10 expression however. Additionally, the IL-12 homologs IL-23 and IL-27 also do not regulate NK cell-specific IL-10. We determined that a small population of NK cells accounts for IL-10 production. The induction of IL-10 by IL-2+IL-12 treatment in NK cells appears to be biphasic, with an initial burst of expression which diminishes by 12h but spikes again at 18h. We determined that much like IFN-γ, Stat4 is largely required for IL-12-induced IL-10. Conversely, we observed normal induction of IL-10 in T-bet-deficient NK cells. We identified a Stat4-binding element in the fourth intron of the Il10 gene, which is completely conserved between mouse and human. This intronic Stat4 motif is within a conserved noncoding sequence, which is also a target for cytokine-induced histone acetylation. These findings highlight tissue- and receptor-specific IL-10 regulatory mechanisms, which may be part of an early feedback loop.
AB - Interleukin-10 (IL-10) is intensely studied, yet little is known about the mechanisms that control IL-10 expression. We identified striking similarities between IL-10 and interferon-γ (IFN-γ) regulation in mouse natural killer (NK) cells. Like IFN-γ, IL-10 expression is induced by IL-2 and IL-12 and IL-2+IL-12 stimulation is synergistic. Unlike IFN-γ, neither IL-18 nor Ly-49D cross-linking induced IL-10 expression however. Additionally, the IL-12 homologs IL-23 and IL-27 also do not regulate NK cell-specific IL-10. We determined that a small population of NK cells accounts for IL-10 production. The induction of IL-10 by IL-2+IL-12 treatment in NK cells appears to be biphasic, with an initial burst of expression which diminishes by 12h but spikes again at 18h. We determined that much like IFN-γ, Stat4 is largely required for IL-12-induced IL-10. Conversely, we observed normal induction of IL-10 in T-bet-deficient NK cells. We identified a Stat4-binding element in the fourth intron of the Il10 gene, which is completely conserved between mouse and human. This intronic Stat4 motif is within a conserved noncoding sequence, which is also a target for cytokine-induced histone acetylation. These findings highlight tissue- and receptor-specific IL-10 regulatory mechanisms, which may be part of an early feedback loop.
UR - http://www.scopus.com/inward/record.url?scp=44849133855&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44849133855&partnerID=8YFLogxK
U2 - 10.1038/gene.2008.20
DO - 10.1038/gene.2008.20
M3 - Article
C2 - 18401353
AN - SCOPUS:44849133855
VL - 9
SP - 316
EP - 327
JO - Genes and Immunity
JF - Genes and Immunity
SN - 1466-4879
IS - 4
ER -