Effect of histamine on intercellular adhesion molecule-1 expression and production of interferon-γ and interleukin-12 in mixed lymphocyte reaction stimulated with interleukin-18

Hideyuki Itoh, Hideo K. Takahashi, Hiromi Iwagaki, Tadashi Yoshino, Yoshinori Morimoto, Shinya Saito, Takahito Yagi, Tadaatsu Akagi, Masahiro Nishibori, Noriaki Tanaka

Research output: Contribution to journalArticle

22 Citations (Scopus)


Background. Interleukin (IL)-18 was identified as an interferon (IFN)-γ-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-γ 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-γ 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. Conclusion. 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.

Original languageEnglish
Pages (from-to)864-870
Number of pages7
Issue number6
Publication statusPublished - Sep 27 2002


ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this