Impaired hydrogen sulfide synthesis and IL-10 signaling underlie hyperhomocysteinemia-associated exacerbation of colitis

Abstract

Significance Inflammatory bowel diseases (IBDs) are debilitating conditions with no known cure. Recent evidence suggests that elevated intestinal hydrogen sulfide (H 2 S) synthesis promotes healing and reduces inflammation. H 2 S is synthesized from cysteine largely via vitamin B 6 -dependent enzymes. People with IBD are also at increased risk of hyperhomocysteinemia, a condition that is often caused by vitamin B deficiency. Dietary induction of vitamin B deficiency markedly increased serum homocysteine levels and worsened colitis in rodents. The latter was due to the absence of the typical injury-induced elevation of H 2 S synthesis. Interleukin-10 plays a key role in increasing H 2 S synthesis, attenuating the severity of colitis, and reducing serum homocysteine levels. The H 2 S–interleukin 10 axis may be a viable target for therapy of IBD.

Gaseous mediators in resolution of inflammation

“…The ability of H 2 S to affect the expression of so many pro-inflammatory cytokines is likely due to its modulating effects on nuclear factor kappa-light-chainenhancer of activated B cells (NF-B) activity [67]. As described in more detail below, IL-10 also plays an important role in the regulation of H 2 S synthesis [68].…”

Nitric oxide, afferent sensory nerves, and antioxidative enzymes in the mechanism of protection mediated by tricarbonyldichlororuthenium(II) dimer and sodium hydrosulfide against aspirin-induced gastric damage

“…The gaseous mediators hydrogen sulfide (H 2 S), carbon monoxide (CO), and nitric oxide (NO) were reported to afford gastroprotection against injury induced by noxious agents but the mechanism of this beneficial action of these molecules has not been fully elucidated [5][6][7][8][9][10]. All three mediators have been shown to take part in regulation of physiological processes in the gastrointestinal tract and other systems [11][12][13].…”

H2S-releasing drugs: Anti-inflammatory, cytoprotective and chemopreventative potential

“…1). Rats with a diet-induced vitamin B deficiency, which have a diminished capacity to synthesize H2S, also exhibit significantly enhanced accumulation of leukocytes in the affected tissues [7]. Mice that are heterozygous for the cystathionine β-synthase gene also have diminished synthesis of H2S, and they exhibit increased levels of leukocyte adherence to the vascular endothelium, slower leukocyte rolling velocity and increased vascular permeability [8].…”

“…Inhibition of pro-inflammatory cytokine expression most likely occurs by suppression of nuclear factor ĸB (NFĸB) activity by H2S [16]. We recently described a regulatory interaction between IL-10 and H2S [7]. IL-10-deficient mice exhibit impaired H2S synthesis in the colon (and these mice can spontaneously develop colitis) [7,17].…”

“…We recently described a regulatory interaction between IL-10 and H2S [7]. IL-10-deficient mice exhibit impaired H2S synthesis in the colon (and these mice can spontaneously develop colitis) [7,17]. Administration of H2S donors increases IL-10 expression [7,15], while administration of IL-10 to the IL-10-deficient mice restored normal colonic H2S synthesis [7].…”