Analysis on the physiological role histamine in airway inflammation using knock-out mice

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1) Analysis on the mechanism of cell-specific expression of HDC gene L-Histidine decarboxylase (HDC) catalyzes the formation of histamine from L-histidine, and in hematopoletic lineages the gene is expressed only in mast cells and basophils. We attempted to discover how HDC gene expression is restricted in these cells. In cultured cell lines tested, only the mast cells (HMC-1) and basophils (KU-812-F) strongly transcribed the HDC gene but K562 or Hela did not. The promotor region of the HDC gene proved to be sensitive to Dnase in HDC-expressing cells. This sensitivity was proved to depend on the extent of methylation. CpG near transcriptional point in the promoter region of HDC gene in Hela and K562 was almost methylated, in contrast, that was not in HMC-1 or KU-812-F. These results imply that alteration of DNA methylation is one of the mechanisms regulating cell-specific expression of the HDC gene.2) Analysis on allergic inflammation in HDC gene knock-out mice To elucidate the role of histamine in allergic reactions, we made knock-out mice which HDC gene was destructed. These mice are not capable to make histamine and are useful as the experimental model lacking histamine. Using these mice, we analyzed allergic responses and compared them to those in wild type mice. We measured exudation from capillaries in skin after exposure to antigen in sensitized HDC knock-out mice with ovalbumin. The exudation was calculated from amount Evans Blue in tissues, which was injected into vessels before. Result demonstrated that no exudation occurred in immediate allergic reaction in knock out mouse. After administrating food containing histamine, knock-out mice showed exudation in immediate allergic reaction. These results clearly indicated that exudation from vessels in allergic reaction was caused by histamine.