Histamine H(2) receptor-mediated modulation of local cytokine expression in a mouse experimental tumor model.
Accumulating evidence indicates that histamine is involved in the modulation of cytokine expression patterns. We previously reported that daily treatment with the H(2) receptor antagonist, cimetidine, suppressed tumor growth through alteration of the local cytokine expression pattern. In this study, we used a mouse strain genetically lacking histidine decarboxylase (HDC), to evaluate the role of endogenous histamine synthesis on cytokine expression and tumor development. In the mutant mice, cimetidine had no effect on tumor growth, whereas an H(2) agonist, dimaprit, significantly enhanced tumor growth. When the HDC-deficient mice were implanted with mutant CT-26 cells stably expressing HDC, drastic suppression of tumor growth by cimetidine was observed, which was accompanied by augmentation of mRNA expression of LT-beta, TNF-alpha, and IFN-gamma in the tumor tissues. These results suggest that endogenous histamine synthesis in tumor tissues suppresses local tumor immunity via the H(2) receptors, resulting in tumor growth promotion.
Takahashi
Kohji
K
Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, 606-8501, Kyoto, Japan.
Tanaka
Satoshi
S
Furuta
Kazuyuki
K
Ichikawa
Atsushi
A
D000818:Animals; D002455:Cell Division; D002927:Cimetidine / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis*; D006632:Histamine / Q000096:biosynthesis; D006640:Histidine Decarboxylase / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000378:metabolism; D053308:Lymphotoxin-beta; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000737:chemistry* / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; C505887:Ltb protein, mouse; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D012333:RNA, Messenger; D011970:Receptors, Histamine H2; D014409:Tumor Necrosis Factor-alpha; D002927:Cimetidine; D006632:Histamine; D007371:Interferon-gamma; D012260:Ribonucleases; D006640:Histidine Decarboxylase