A novel immunoregulatory function for IL-23: Inhibition of IL-12-dependent IFN-γ production.
Most studies investigating the function of IL-23 have concluded that it promotes IL-17-secreting T cells. Although some reports have also characterized IL-23 as having redundant pro-inflammatory effects with IL-12, we have instead found that IL-23 antagonizes IL-12-induced secretion of IFN-γ. When splenocytes or purified populations of T cells were cultured with IL-23, IFN-γ secretion in response to IL-12 was dramatically reduced. The impact of IL-23 was most prominent in CD8(+) T cells, but was also observed in NK and CD4(+) T cells. Mechanistically, the IL-23 receptor was not required for this phenomenon, and IL-23 inhibited signaling through the IL-12 receptor by reducing IL-12-induced signal transducer and activator of transcription 4 (STAT4) phosphorylation. IL-23 was also able to reduce IFN-γ secretion by antagonizing endogenously produced IL-12 from Listeria monocytogenes (LM)-infected macrophages. In vivo, LM infection induced higher serum IFN-γ levels and a greater percentage of IFN-γ(+)CD8(+) T cells in IL-23p19-deficient mice as compared with WT mice. This increase in IFN-γ production coincided with increased LM clearance at days 2 and 3 post-infection. Our data suggest that IL-23 may be a key factor in determining the responsiveness of lymphocytes to IL-12 and their subsequent secretion of IFN-γ.
Sieve
Amy N
AN
Department of Molecular Biology and Immunology, The University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Meeks
Karen D
KD
Lee
Suheung
S
Berg
Rance E
RE
D000818:Animals; D058491:Bacterial Load / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation; D056747:Immunomodulation; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics / Q000494:pharmacology*; D008088:Listeriosis / Q000276:immunology* / Q000382:microbiology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053707:Receptors, Interleukin-12 / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D053759:Interleukin-23; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma
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