Essential role of ICAM-1/LFA-1 interaction in synergistic effect of IL-18 and IL-12 on IFN-gamma production in human PBMC.
IL-18 (0-100 ng/ml) specifically upregulated ICAM-1 expression on monocytes in human PBMC as demonstrated in our previous study. In the present study, we examined whether the synergistic upregulation of ICAM-1 occurred after the stimulation with the combination of IL-18 and IL-12 and whether the synergistic production of IFN-gamma was dependent on the interaction between ICAM-1 on monocytes and LFA-1 on NK/T cells. The effect of IL-12 on ICAM-1 expression on monocytes was marginal even at the highest concentration (100 ng/ml). However, in the presence of IL-12 (100 ng/ml), the expression of ICAM-1 induced by IL-18 was significantly enhanced as compared with that obtained by IL-18 alone. In addition to the expression of ICAM-1 on monocytes, IFN-gamma production was synergistically stimulated by IL-18 and IL-12. Anti-ICAM-1 and anti-LFA-1 Abs exhibited significant inhibitory effect on enhanced production of IFN-gamma by the combination of two cytokines, in particular, anti-ICAM-1 showing the complete inhibition. These results as a whole indicated that synergistic effect of IL-18 and IL-12 on IFN-gamma production in human PBMC is ascribed to the synergism of the effect of two cytokines on ICAM-1 expression on monocytes and that the subsequent ICAM-1/LFA-1 interaction plays an important role in the enhanced production of IFN-gamma.
Yoshida
Atsushi
A
Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Kohka Takahashi
Hideo
H
Iwagaki
Hiromi
H
Yoshino
Tadashi
T
Morichika
Toshihiko
T
Yokoyama
Minori
M
Itoh
Hideyuki
H
Mori
Shuji
S
Akagi
Tadaatsu
T
Nishibori
Masahiro
M
Tanaka
Noriaki
N
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis* / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D020382:Interleukin-18; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; D007371:Interferon-gamma