Inflammatory bowel disease (IBD) represents a spectrum of diseases in which inflammation leads to acute and chronic gut injury. It is a growing health issue for which no cure exists. The pathogenesis is multifactorial with links to infectious and environmental events that trigger disease in genetically predisposed individuals. Treatment of the two major forms of IBD, Crohn's disease and ulcerative colitis, involves the reduction of inflammation with toxic immunosuppressive drugs or blocking of the pro-inflammatory effects of tumour necrosis factor-alpha (TNF-alpha) with antibodies. Here, we show that the oral administration of transgenic low-alkaloid tobacco expressing the contra-inflammatory cytokine human interleukin-10 (hIL-10) reduces the severity of colitis by down-regulating TNF-alpha expression directly at the sites of inflammation in IBD-susceptible IL-10(-/-) mice. hIL-10 expressed in plants is biologically active and displays resistance to gastrointestinal degradation. Dietary supplementation with plant tissue delivering up to 9 microg of hIL-10 daily for 4 weeks was well tolerated by treated mice. Gut histology was significantly improved relative to controls (P = 0.002), and was correlated with a decrease in small bowel TNF-alpha mRNA levels and an increase in IL-2 and IL-1beta mRNA levels. Transgenic plants expressing IL-10 to directly attenuate TNF-alpha expression at sites of inflammation in the gut may become a useful new approach in the luminal therapy of IBD.