![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Departments of Pharmacology (H.K.T., A.Y., M.N.), Gastroenterological Surgery, Transplant, and Surgical Oncology (H.I., N.T.), and Pathology (T.Y.), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; and RIKEN Yokohama Institute Yokohama Research Promotion Division, Yokohama, Kanagawa, Japan (T.W.)
Received April 20, 2006; accepted May 24, 2006
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResults and DiscussionReferences |
|---|
). This action may be due to a direct inhibitory effect on tumor growth (Adams and Morris, 1994), cell-mediated immunomodulation (Hellstrand and Hermodsson, 1986; Gifford and Tirberg, 1987), or inhibition of cancer cell metastases (Tomita et al., 2003). The cell-mediated immunomodulation includes inhibition of suppressor T cells (Hellstrand and Hermodsson, 1986), stimulation of natural killer cells, and increase in IL-2 production in T cells (Gifford and Tirberg, 1987). The increase of histamine release is reported to represent the underlying cause for immunosuppression observed at the time of colonic resection; such an effect exerted by histamine can be prevented by perioperative cimetidine (Adams and Morris, 1994). However, such beneficial effects using other H2R antagonists (i.e., famotidine and ranitidine), have not been observed in clinical trials (Matsumoto, 1995). Cimetidine treatment inhibits histamine-initiated angiogenesis via reducing vascular endothelial growth factor expression (Gifford and Tirberg, 1987). The activation state of intratumoral DC is a critical factor in the host response to tumors (Furumoto et al., 2004). Cimetidine-induced higher antigen presenting capacity of DC was observed in patients with advanced cancer compared with healthy control subjects (Kubota et al., 2002).
IL-18, a monocyte-derived cytokine that requires cleavage with caspase-1 for activity (Gu et al., 1997), enhances local antitumor immune responses through activating natural killer cells and T cells (Kohno et al., 1997). IL-18 inhibits angiogenesis (Coughlin et al., 1998) and induces apoptosis in tumor cells (Hashimoto et al., 1999). In the mouse colon cancer model, IL-18 inhibits growth of cells (Tamura et al., 2003), and successful prevention of colon cancer establishment is associated with elevation of serum IL-18 level (Goto et al., 2002). In the present study, cimetidine behaved as a partial agonist for H2R in inducing IL-18 production in monocytes and DC derived from PBMC.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResults and DiscussionReferences |
|---|
Preparation of Human and Murine Cells. Normal human PBMC were obtained from peripheral blood of 10 volunteers after acquiring institutional review board approval (Okayama University; IRB 279) as described previously (Kohka et al., 2000). Separation of monocytes from PBMC was carried out as described previously (Takahashi et al., 2003). The purity of monocytes was 85% as determined by flow cytometry with anti-CD14 antibody. DC were prepared from PBMC as described previously (Kubo et al., 2004). The resultant DC showed CD1a(+)CD14(-)HLA-DR(+)CD83(-) phenotype, consistent with the previous report (Kubo et al., 2004). PBMC and spleen cells were obtained from five wild-type or H2R knockout mice as described previously (Yokoyama et al., 2004). We abided by the guidelines on animal experimentation of Okayama University Graduate School of Medicine and Dentistry, and the institutional animal experimentation review committee licensed all procedures.
Cytokine Assays. IL-18 in cell-free supernatants was measured by enzyme-linked immunosorbent assay kit (for human and mouse IL-18; MBL) as described previously (Kohka et al., 2000; Takahashi et al., 2003). The detection limit of the enzyme-linked immunosorbent assay was 10 pg/ml.
Activity of Caspase-1. The activity of caspase-1 was determined in a colorimetric assay with a substrate (WEHD-pNA) specific for this enzyme (R&D Systems, Inc., Minneapolis, MN). After 1-h incubation, monocytes were pelleted by centrifuging (1000g; 4°C, 5 min), the supernatant was aspirated, and the cells were lysed in accordance with the manufacturer's instructions. Cell lysate and the initial supernatant were analyzed for the activity of cell-bound and released caspase-1, respectively.
|
). We performed no acetylation procedures. Statistical Examination. The statistical significance of differences was evaluated by analysis of variance followed by Dunnett's test. The results are presented as the means ± S.E.M. of triplicate findings from five donors. A probability value (P) less than 0.05 was considered significant.
|
Results and Discussion |
|---|
|
TopAbstractMaterials and MethodsResults and DiscussionReferences |
|---|
). The concentration range of cimetidine has been used for assessing the H2R antagonistic activity of cimetidine on different tissue preparations including stomach and atrium. Other H2R antagonists (i.e., famotidine and ranitidine) had no effect on the production of IL-18 (Fig. 1B). Cimetidine at 100 µM induced the production of IL-18 in the presence of histamine at 0.01 µM; however, the same concentration of cimetidine inhibited the production of IL-18 induced by histamine at 1 and 100 µM (Fig. 1C). Therefore, cimetidine may act as a partial agonist in the presence of histamine at 0.01 µM, whereas it may act as an antagonist in the presence of histamine at 1 and 100 µM. The amount of histamine in the conditioned media of monocytes treated with cimetidine was the same as control cells without cimetidine. Moreover, histamine at the concentration present in such conditioned media did not have any effect on cytokine production. These results indicate that the effect of cimetidine was not mediated via antagonism of histamine action on H2R and that cimetidine may behave as an agonist when the concentration of histamine is low. This finding prompted us to test whether cimetidine exerted its effect by acting as an agonist for H2R stimulation.
|
; van der Pouw Kraan et al., 1998). Cimetidine as well as histamine induced the elevation of cAMP (Fig. 2C); however, famotidine and ranitidine had no effect (data not shown). The maximal effect of cimetidine on cAMP elevation was one third of that obtained by histamine. As shown in Fig. 2D, the PKA inhibitor H89 partially inhibited the cimetidine- and histamine-induced IL-18 production by 56 and 58%, respectively. These results suggested that the cAMP/PKA pathway is partially involved in the action of cimetidine. In addition, we examined the effect of cimetidine and histamine on the production of IL-18 by spleen cells and PBMC from H2R knockout mice (Fig. 2, E and F). Cimetidine and histamine induced the production of IL-18 by the cells from wild-type mice but not from H2R knockout mice. Taken together, the present findings indicate that cimetidine stimulated H2R as a partial agonist. Burimamide is reported to be a partial H2R agonist at the recombinant human H2R (Alewijnse et al., 1998); however, burimamide had no effect on the production of IL-18 by human monocytes (Fig. 1B). On the other hand, cimetidine was classified as an inverse agonist using the recombinant human H2R transfected into Chinese hamster ovary cells (Alewijnse et al., 1998). Thus, the pharmacological profile of H2R antagonists may differ depending on the receptor expression cells. In conclusion, cimetidine induces the production of IL-18 in monocytes via H2R, and this may provide insights into mechanism underlying the improvement of the prognoses of patients with colon cancer as a result of cimetidine treatment.
|
Footnotes |
|---|
ABBREVIATIONS: IL, interleukin; H2R, histamine receptor type2; H89, N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline; PBMC, peripheral blood mononuclear cell; DC, dendritic cell; Z-YVAD-FMK, N-benzyloxycarbonyl-Tyr-Val-Ala-Asp-fluoromethyl ketone; PKA, protein kinase A.
Address correspondence to: Dr. Masahiro Nishibori, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. E-mail: mbori{at}md.okayama-u.ac.jp
|
References |
|---|
|
TopAbstractMaterials and MethodsResults and DiscussionReferences |
|---|
Alewijnse AE, Smit MJ, Hoffmann M, Verzijl D, Timmerman H, and Leurs R (1998) Constitutive activity and structural instability of the wild-type human H2 receptor. J Neurochem 71: 799-807.[Medline]
Coughlin CM, Salhany KE, Wysocka M, Aruga E, Kurzawa H, Chang AE, Hunter CA, Fox JC, Trinchieri G, and Lee WM (1998) Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis. J Clin Investig 101: 1441-1452.[Medline]
Furumoto K, Soares L, Engleman EG, and Merad M (2004) Induction of potent antitumor immunity by in situ targeting of intratumoral DCs. J Clin Investig 113: 774-783.[CrossRef][Medline]
Gifford RRM and Tirberg AF (1987) Histamine type-2 receptor antagonistimmune modulation II. Cimetidine and ranitidine increase interleukin-2 production. Surgery 102: 242-247.[Medline]
Goto H, Osaki T, Nishino K, Tachibana I, Takeda Y, Yoneda T, Funakoshi T, Kimura H, Hayashi S, and Tahara H (2002) Construction and analysis of new vector systems with improved interleukin-18 secretion in a xenogeneic human tumor model. J Immunother 25 (Suppl 1): S35-S41.[Medline]
Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K, Okamura H, Nakanishi K, et al. (1997) Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science (Wash DC) 275: 206-209.
Hashimoto W, Osaki T, Okamura H, Robbins PD, Kurimoto M, Nagata S, Lotze MT, and Tahara H (1999) Differential antitumor effects of administration of recombinant IL-18 or recombinant IL-12 are mediated primarily by Fas-Fas ligand- and perforin-induced tumor apoptosis, respectively. J Immunol 163: 583-589.
Hellstrand K and Hermodsson S (1986) Histamine H2-receptor-mediated regulation of human natural killer cell activity. J Immunol 137: 656-660.[Abstract]
Kohka H, Nishibori M. Iwagaki H, Nakaya N, Yoshino T, Kobashi K, Saeki K, Tanaka N, and Akagi T (2000) Histamine is a potent inducer of IL-18 and IFN-gamma in human peripheral blood mononuclear cells. J Immunol 164: 6640-6646.
Kohno K, Kataoka J, Ohtsuki T, Suemoto Y, Okamoto I, Usui M, Ikeda M, and Kurimoto M (1997) IFN-gamma-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J Immunol 158: 1541-1550.[Abstract]
Kubo S, Takahashi HK, Takei M, Iwagaki H, Yoshino T, Tanaka N, Mori S, and Nishibori M (2004) EP (E-Prostanoid)2/EP4-receptor-dependent maturation of human monocyte-derived dendritic cells and induction of Th2 polarization. J Pharmacol Exp Ther 309: 1213-1220.
Kubota T, Fujiwara H, Ueda Y, Itoh T, Yamashita T, Yoshimura T, Okugawa K, Yamamoto Y, Yano Y, and Yamagishi H (2002) Cimetidine modulates the antigen presenting capacity of dendritic cells from colorectal cancer patients. Br J Cancer 86: 1257-1261.[Medline]
Matsumoto S (1995) Cimetidine and survival with colorectal cancer. Lancet 346: 115.[Medline]
Shayo C, Davio C, Brodsky A, Mladovan AG, Legnazzi BL, Rivera E, and Baldi A (1997) Histamine modulates the expression of c-fos through cyclic AMP production via the H2 receptor in the human promonocytic cell line U937. Mol Pharmacol 51: 983-990.
Takahashi HK, Iwagaki H, Tamura R, Xue D, Sano M, Mori S, Yoshino T, Tanaka N, and Nishibori M (2003) Unique regulation profile of prostaglandin E1 on adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells. J Pharmacol Exp Ther 307: 1188-1195.
Tamura T, Nishi T, Goto T, Takeshima H, Ushio Y, and Sakata T (2003) Combination of IL-12 and IL-18 of electro-gene therapy synergistically inhibits tumor growth. Anticancer Res 23: 1173-1179.[Medline]
Tomita K, Izumi K, and Okabe S (2003) Roxatidine- and cimetidine-induced angiogenesis inhibition suppresses growth of colon cancer implants in syngeneic mice. J Pharmaco Sci 93: 321-330.[CrossRef]
Tonnesen T, Knigge U, Bulow S, Bulow S, Damm P, Fischerman K, Hesselfeldt HA, Pedersen IK, Pedersen VM, Siemssen OJ, et al. (1988) Effect of cimetidine on survival after gastric cancer. Lancet 2: 990-991.[Medline]
van der Pouw Kraan TC, Snijders A, Boeije LC, de Groot ER, Alewijnse AE, Leurs R, and Aarden LA (1998) Histamine inhibits the production of interleukin-12 through interaction with H2 receptors. J Clin Investig 102: 1866-1873.[Medline]
Yokoyama M, Yokoyama A, Mori S, Takahashi HK, Yoshino T, Watanabe T, Watanabe T, Ohtsu H, and Nishibori M (2004) Inducible histamine protects mice from P. acnes-primed and LPS-induced hepatitis through H2-receptor stimulation. Gastroenterology 127: 892-902.[CrossRef][Medline]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
) or cimetidine (CIM; 
) at concentrations ranging from 10 nM to 1 mM for 24 h. B, monocytes at 1 x 106 cells/ml were treated with CIM, famotidine (FAM), ranitidine (RAN), or brimamide (BRI) at 1 or 100 µM, and DC at 1 x 106 cells/ml were treated with CIM or HA for 24 h. ND, not detected. **, P < 0.01 compared with the corresponding value for medium alone. C, monocytes at 1 x 106 cells/ml were treated with CIM at 100 µMin the presence of HA at 0.01, 1 or 100 µM for 24 h. **, P < 0.01 compared with the corresponding value for medium alone. ##, P < 0.01 compared with the corresponding value for histamine. D, activity of caspase-1. Monocytes at 2 x 106 cells/ml were treated with cimetidine and histamine at 1 or 100 µM for 1 h. **, P < 0.01 compared with the corresponding value for medium alone. E, monocytes at 1 x 106 cells/ml were treated with cimetidine or histamine at 100 µM in the presence or absence of Z-YVAD-FMK at 100 µM for 24 h. **, P < 0.01 compared with the corresponding value in the presence of cimetidine or histamine alone.
) at 100 µM for 24 h. **, P < 0.01 compared with the corresponding value for histamine alone. #, P < 0.05; ##, P < 0.01 compared with the corresponding value for cimetidine alone. E and F, spleen cells or PBMC from wild-type or H2-receptor knockout mice at 1 x 106 cells/ml were treated with cimetidine (E) or histamine (F) at 1 and 100 µM for 24 h. **, P < 0.01 compared with the corresponding value in medium alone. ND, not detected. When an error bar was within a symbol, the bar was omitted.