Inhibition of GTP cyclohydrolase enhances intestinal inflammation in mice

Background and aims: GTP cyclohydrolase (GCH1) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis which is an essential cofactor for catecholamine, serotonin and nitric oxide production. GCH1 is a key modulator of peripheral neuropathic and inflammatory pain. However, the role of GCH1 in the intestinal inflammation is not well understood.

Methods and results: We studied the role of GCH1 by using the GCH1 inhibitor, diaminohydropyrimidine (DAHP) in a mouse model of dextran sodium sulphate induced colitis. Mice were challenged with 2.5% DSS for 10 days to induce colitis and were treated with DAHP by oral gavage. Suppression of BH4 synthesis with the GCH1 inhibitor enhanced the development of colonic inflammation. DAHP treated mice have severe inflammation, indicating more weight lost and epithelial erosions compared with control mice. Blockade of GCH1 increased the infiltration of inflammatory cells (polymorphonuclear leukocytes) in the colonic mucosa. In vivo luciferase imaging revealed an aggravation of inflammation in mice treated with DAHP. Furthermore, inhibition of GCH1 in colitogenic mice is associated with elevated levels of lipid mediators in inflamed tissue and in plasma.

Conclusions: GTP cyclohydrolase (GCH1) is the key-enzyme to produce the essential enzyme cofactor, tetrahydrobiopterin. Inhibition of GCH1 enhances intestinal inflammation in the mouse model of DSS induced colitis. Increased inflammation is accompanied by elevated proinflammatory immune response.