Effect of histamine on intercellular adhesion molecule-1 expression and production of interferon-gamma and interleukin-12 in mixed lymphocyte reaction stimulated with interleukin-18.
BACKGROUND
Interleukin (IL)-18 was identified as an interferon (IFN)-gamma-inducing factor and was demonstrated to up-regulate the expression of intercellular adhesion molecule (ICAM)-1 on human monocytes. In organ transplantation, elevation of plasma IL-18 levels has been reported during acute rejection. In the present study, we examined the effect of IL-18 on human mixed lymphocyte reaction (MLR), an in vitro model of acute rejection after organ transplantation. We also investigated the modulatory effects of histamine on IL-18 action because histamine has been demonstrated to be a modulator of IL-18 effect and a mediator of inflammation.


METHODS
We measured the expression of ICAM-1 on human monocytes in MLR in the presence or absence of IL-18 by flow cytometer and determined the associated production of IFN-gamma and IL-12 by ELISA. The modulatory effects of histamine and the relevant histamine receptor subtypes were characterized pharmacologically.


RESULTS
The expression of ICAM-1 on monocytes in MLR was markedly enhanced by the addition of IL-18 in a concentration- and time-dependent manner. In parallel to ICAM-1 up-regulation, IL-18 significantly enhanced the production of IFN-gamma and IL-12 in MLR. Histamine concentration-dependently inhibited ICAM-1 expression and cytokine production in MLR stimulated with IL-18, whereas histamine alone did not show any effects on these responses in the absence of IL-18. The effects of histamine on both ICAM-1 expression and cytokine production were mimicked by the selective H2-receptor agonists 4-methylhistamine and dimaprit and were antagonized by the H2-receptor antagonist famotidine but not by H1- and H3-receptor antagonists.


CONCLUSIONS
IL-18 strongly enhanced human MLR with respect to ICAM-1 expression and cytokine production. The fact that histamine could inhibit the IL-18-stimulated MLR implies that immunomodulation by histamine and selective H2-receptor agonists may have an important role in future immunosuppressive strategies.
D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D007165:Immunosuppression Therapy; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis*; D020382:Interleukin-18 / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011968:Receptors, Histamine / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
D020382:Interleukin-18; D011948:Receptors, Antigen, T-Cell; D011968:Receptors, Histamine; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; D006632:Histamine; D007371:Interferon-gamma