A mechanism underlying synergy between IL-12 and IFN-gamma-inducing factor in enhanced production of IFN-gamma.
IL-12 and IFN-gamma-inducing factor (IGIF) have the capacity to stimulate IFN-gamma production by T cells. Using an IL-12-responsive T cell clone, 2D6, we investigated how these two cytokines collaborate for IFN-gamma production. 2D6 obtained from cultures containing rIL-12 produced IFN-gamma in response to rIGIF. 2D6 from cultures deprived of IL-12 for 24 h produced only marginal levels of IFN-gamma production following stimulation with either rIL-12 or rIGIF alone. However, simultaneous stimulation of these 2D6 cells with both cytokines resulted in strikingly enhanced levels of IFN-gamma production. 2D6 could also be maintained in the presence of rIL-2 instead of rIL-12. 2D6 lines maintained with rIL-12 (2D6(IL-12)) or rIL-2 (2D6(IL-2)) exhibited differential IGIF responsiveness: both lines responded similarly to rIL-2 or rIL-12, whereas the 2D6(IL-12) or 2D6(IL-2) exhibited high or marginal IGIF responsiveness, respectively. The 2D6(IL-12) line expressed IGIF receptor (IGIFR), whereas the 2D6(IL-2) did not. Overnight exposure of the 2D6(IL-12) to rIL-2 reduced IGIFR expression and conversely, exposure of the 2D6(IL-2) to rIL-12 restored IGIFR expression. IGIFR expression by these 2D6 lines correlated with the capacity to produce IFN-gamma in response to rIGIF. Purified naive T cells stimulated with anti-CD3 plus anti-CD28 mAb and subsequently cultured with rIL-12 were also found to express IGIFR and induce enhanced IFN-gamma production following IGIF stimulation. These results indicate that the induction of IGIFR by IL-12 represents one of the mechanisms underlying the synergy between IL-12 and IGIF in IFN-gamma production.
Ahn
H J
HJ
Biomedical Research Center, Osaka University Medical School, Suita, Japan.
Maruo
S
S
Tomura
M
M
Mu
J
J
Hamaoka
T
T
Nakanishi
K
K
Clark
S
S
Kurimoto
M
M
Okamura
H
H
Fujiwara
H
H
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D016207:Cytokines; D020382:Interleukin-18; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma