Similarly, our data show that LPS treatment in the colon causes severe inflammation in the small intestine remotely, while it induces proinflammatory cytokine production in the colon without causing adverse effects on the colonic mucosa (Figs. 1 and and2).2). Regarding the small intestinal inflammation remotely www.selleckchem.com/products/mek162.html induced by colonic LPS, we speculate that lamina propria cells in the colon might respond to colonic LPS, or epithelial cells in the colon could be able to sense luminal LPS, to induce inflammatory mediators, which will trigger subsequent inflammatory responses in the small intestine. In answer to question 2, various examples of the protective mechanism against LPS can be proposed. Secretory IgA antibody in the intestine serves as an external barrier to neutralize LPS in the intestine (8).

In addition, the colonic epithelium is rich in mucin-producing goblet cells, and the mucus layer can prevent LPS attachment to the mucosal surface in the colon (21). Although transmural passage of LPS was suggested to be almost imperceptible in the normal colon (23), LPS can be absorbed at a molecular level by a specific cellular transporter, the chylomicron, in the intestinal epithelial cells and, thereby, can induce inflammatory responses (13). In this case, however, immune-suppressive Treg cells and an anti-inflammatory cytokine, such as IL-10, can engage in modulating inflammatory responses (9�C11). Moreover, TLR-inhibitory molecules [e.g.

, Toll-interacting protein (TOLLIP), IL-1 receptor-associated kinase (IRAK-M), single immunoglobulin IL-1 receptor-related protein (SIGIRR), splice variant of myeloid differentiation factor 88 (MyD88s), and TIR domain-containing adaptor-inducing Cilengitide IFN-�� (TRIF)] are strongly expressed or can be upregulated by inflammatory responses in intestinal epithelial cells and, subsequently, can disrupt a prolonged inflammatory response (5). Taken together, although colonic LPS is able to elicit inflammatory responses initially, these protective mechanisms may allow the intestine to contain the inflammatory response. Although we appreciate that a clear answer is not straightforward, thanks to some of these protective mechanisms, mice treated with colonic LPS could recover from the intestinal inflammation. This speculation can be supported by our findings that 1) intestinal inflammation was severe in IL-10?/? mice, and they failed to recover (Fig. 4), and 2) T cell-depleted Rag-1?/? mice could not recover from LPS-induced intestinal inflammation (Fig. 5). We, however, acknowledge that the exact mechanism by which LPS in the colon can induce small intestinal inflammation remotely but does not damage the colonic epithelium locally is still not clear.