IL-4 induces in vivo production of IFN-gamma by NK and NKT cells.
Although IL-4 and IFN-gamma often have opposite effects and suppress each other's production by T cells, IL-4 can stimulate IFN-gamma production. To characterize this, we injected mice with IL-4 and quantified IFN-gamma production with the in vivo cytokine capture assay. IL-4 induced Stat6-dependent IFN-gamma production by NK and, to a lesser extent, NKT cells, but not conventional T cells, in 2-4 h. Increased IFN-gamma production persisted at a constant rate for >24 h, but eventually declined, even with continuing IL-4 stimulation. This eventual decline in IFN-gamma production was accompanied by a decrease in NK and T cell numbers. Consistent with a dominant role for NK cells in IL-4-stimulated IFN-gamma secretion, IL-4 induction of IFN-gamma was B and T cell-independent; suppressed by an anti-IL-2Rbeta mAb that eliminates most NK and NKT cells; reduced in Stat4-deficient mice, which have decreased numbers of NK cells; and absent in Rag2/gamma(c)-double-deficient mice, which lack T, B, and NK cells. IL-4-induced IFN-gamma production was not affected by neutralizing IL-12p40 and was increased by neutralizing IL-2. IL-13, which signals through the type 2 IL-4R and mimics many IL-4 effects, failed to stimulate IFN-gamma production and, in most experiments, suppressed basal IFN-gamma production. Thus, IL-4, acting through the type 1 IL-4R, induces Stat6-dependent IFN-gamma secretion by NK and NKT cells. This explains how IL-4 can contribute to Th1 cytokine-associated immune effector functions and suggests how IL-13 can have stronger proallergic effects than IL-4.
Morris
Suzanne C
SC
Division of Immunology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. morrissc@email.uc.edu
Orekhova
Tatyana
T
Meadows
Michelle J
MJ
Heidorn
Stephanie M
SM
Yang
Junqi
J
Finkelman
Fred D
FD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis*; D053631:Interleukin Receptor Common gamma Subunit; D018664:Interleukin-12 / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D007376:Interleukin-2; C499308:Rag2 protein, mouse; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma