Histamine H₂ 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 H₂ 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 H₂ 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-β, TNF-α, and IFN-γ in the tumor tissues. These results suggest that endogenous histamine synthesis in tumor tissues suppresses local tumor immunity via the H₂ receptors, resulting in tumor growth promotion.