title: Stat4-dependent, T-bet-independent regulation of IL-10 in NK cells.
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.
authors.affiliation: W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205-1901, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Grant
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Yao
authors.forename: C M
authors.initials: CM
authors.lastname: Hedrich
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Moorthy
authors.forename: K
authors.initials: K
authors.lastname: Wilson
authors.forename: D
authors.initials: D
authors.lastname: Ranatunga
authors.forename: J H
authors.initials: JH
authors.lastname: Bream
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D004357:Drug Synergism; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D013268:Stimulation, Chemical; D020825:T-Box Domain Proteins / Q000502:physiology*; D013997:Time Factors; D000098815:T-bet Transcription Factor
chemical_list: D007376:Interleukin-2; D012333:RNA, Messenger; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma