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PMID: 18401353 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Stat4-dependent, T-bet-independent regulation of IL-10 in NK cells.

Genes and immunity ·Vol. 9 ·No. 4 ·2008-06-00 ·Pages 316-27

Grant LR, Yao ZJ, Hedrich CM, Wang F, Moorthy A, Wilson K, Ranatunga D, Bream JH

Abstract

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-gamma (IFN-gamma) regulation in mouse natural killer (NK) cells. Like IFN-gamma, IL-10 expression is induced by IL-2 and IL-12 and IL-2+IL-12 stimulation is synergistic. Unlike IFN-gamma, 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 12 h but spikes again at 18 h. We determined that much like IFN-gamma, 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.

MeSH Terms
Animals Cell Culture Techniques Cells, Cultured Drug Synergism Interferon-gamma/metabolism Interleukin-10/biosynthesis,genetics Interleukin-12/pharmacology Interleukin-2/pharmacology Killer Cells, Natural/immunology,metabolism Kinetics Mice Mice, Inbred C57BL RNA, Messenger/analysis,metabolism STAT4 Transcription Factor/chemistry,genetics,metabolism Spleen/cytology Stimulation, Chemical T-Box Domain Proteins/physiology Time Factors
Chemicals
Interleukin-2 RNA, Messenger STAT4 Transcription Factor T-Box Domain Proteins T-box transcription factor TBX21 Interleukin-10 Interleukin-12 Interferon-gamma
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Grant L R
W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205-1901, USA.
Yao Z-J
Hedrich C M
Wang F
Moorthy A
Wilson K
Ranatunga D
Bream J H
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Article Info
Journal
Genes and immunity
Abbr.
Genes Immun
ISSN
1476-5470
DOI
10.1038/gene.2008.20
Published
2008-06-00
Epub
2008-00-10
Pages
316-27
Language
English
Region
England
NLM ID
100953417
PMCID
PMC2689787
Subset
IM
Grants
NIAID NIH HHS · R01 AI070594 · United States
NIAID NIH HHS · R01 AI070594-02 · United States
NIAID NIH HHS · R56 AI070594 · United States
NIAID NIH HHS · AI070594 · United States
External Links
PubMed source DOI: 10.1038/gene.2008.20 PMC Full Text View journal details
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