Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer (CRC)1. This association could be explained by the hypothesis that the same factors and pathways important for wound healing also promote tumorigenesis. A sensor of tissue damage should induce these factors to promote tissue repair and regulate their action to prevent development of cancer. IL-22, a cytokine of the IL-10 superfamily, plays an important role for colonic epithelial cell repair, and is increased in the blood and intestine of IBD patients2, 3. This cytokine can be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP, IL-22RA2), however the significance of endogenous IL-22BP in vivo and the pathways that regulate this receptor are unknown4, 5. We describe herein that IL-22BP plays a crucial role in controlling tumorigenesis and epithelial cell proliferation in the colon. IL-22BP is highly expressed by dendritic cells (DC) in the colon in steady state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes led to an IL-18-dependent down regulation of IL-22BP, thereby increasing the ratio of IL-22/IL-22BP. IL-22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumor development if uncontrolled during the recovery phase.Thus the IL-22-IL-22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease thought to be mediated by dysfunctional innate and/or adaptive immunity. This aberrant immune response leads to the secretion of harmful cytokines that destroy the epithelium of the gastrointestinal tract leading to further inflammation. IL-22 is a Th17 T cell associated cytokine that is bi-functional with both pro-inflammatory and protective effects on tissues depending on the inflammatory context. We show herein that IL-22 protects mice from IBD. Interestingly, this protection is not only mediated by CD4 T cells, but IL-22 expressing NK cells also confer protection. In addition, IL-22 expression is differentially regulated between NK cell subsets. Thus, both the innate and adaptive immune responses have developed protective mechanisms to counteract the damaging effects of inflammation on tissues.

The cytokine interleukin-22 (IL-22) is primarily expressed by T helper 17 (Th17) CD4(+) T cells and is highly upregulated during chronic inflammatory diseases. IL-22 receptor expression is absent on immune cells, but is instead restricted to the tissues, providing signaling directionality from the immune system to the tissues. However, the role of IL-22 in inflammatory responses has been confounded by data suggesting both pro- and anti-inflammatory functions. Herein, we provide evidence that during inflammation, IL-22 played a protective role in preventing tissue injury. Hepatocytes from mice deficient in IL-22 were highly sensitive to the detrimental immune response associated with hepatitis. Additionally, IL-22-expressing Th17 cells provided protection during hepatitis in IL-22-deficient mice. On the other hand, interleukin-17 (IL-17), which is coexpressed with IL-22 and can induce similar cellular responses, had no observable role in liver inflammation. Our data suggest that IL-22 serves as a protective molecule to counteract the destructive nature of the immune response to limit tissue damage.

Multidrug resistance pumps (MDRs) protect microbial cells from both synthetic and natural antimicrobials. Amphipathic cations are preferred substrates of MDRs. Berberine alkaloids, which are cationic antimicrobials produced by a variety of plants, are readily extruded by MDRs. Several Berberis medicinal plants producing berberine were found also to synthesize an inhibitor of the NorA MDR pump of a human pathogen Staphylococcus aureus. The inhibitor was identified as 5-methoxyhydnocarpin (5-MHC), previously reported as a minor component of chaulmoogra oil, a traditional therapy for leprosy. 5-MHC is an amphipathic weak acid and is distinctly different from the cationic substrates of NorA. 5-MHC had no antimicrobial activity alone but strongly potentiated the action of berberine and other NorA substrates against S. aureus. MDR-dependent efflux of ethidium bromide and berberine from S. aureus cells was completely inhibited by 5-MHC. The level of accumulation of berberine in the cells was increased strongly in the presence of 5-MHC, indicating that this plant compound effectively disabled the bacterial resistance mechanism against the berberine antimicrobial.multidrug resistance ͉ efflux inhibitor B acteria have evolved numerous defenses against antimicrobial agents, and drug-resistant pathogens are on the rise (1). A general and effective defense is conferred by ubiquitous multidrug resistance pumps (MDRs), membrane translocases that extrude structurally unrelated toxins from the cell (2-5). Preferred substrates of most MDRs are synthetic hydrophobic cations such as quaternary ammonium antiseptics (6, 7). We have identified a group of cationic berberine alkaloids as natural substrates of MDR pumps (6). We suggested that berberine alkaloids represent a possibly larger group of cationic toxins that fueled the evolution of MDRs (7). Considering that microbial MDRs can render berberine alkaloids essentially ineffective, we reasoned that plants would benefit from making an MDR inhibitor. Here we show that Berberis fremontii, a berberine producer (8) used in Native American traditional medicine (9, 10), synthesizes a potent MDR inhibitor. Structural determination identified the substance as 5Ј-methoxyhydnocarpin (5Ј-MHC). Efflux of berberine from pathogenic Staphylococcus aureus expressing the NorA MDR pump that confers resistance to quinolones and antiseptics (6,11,12) was inhibited completely by 5Ј-MHC. This is a clear example of synergy between components of a medicinal plant described at a molecular level. Materials and MethodsCell Culturing and Susceptibility Testing. S. aureus 4222 parent strain and the norA mutant KLE 820 (6) were cultured in Mueller-Hinton (MH) broth. Cells (10 5 ͞ml) were inoculated into MH broth and dispensed at 0.2 ml͞well in microtiter plates. All tests were done in triplicate by following National Center for Clinical Laboratory Standards recommendations. Briefly, minimal inhibitory concentrations (MIC) were determined by serial 2-fold dilution of test compounds. MIC was defined as a concentr...