In the present study, we found increased IL-6 expression in CECs from mice with DSS-induced colitis (Fig. 1A) and demonstrated selleck chem inhibitor directly that IL-6 induced S100A9 expression in both CECs from mice with colitis and in a human IEC cell line (Fig. 1D, ,4B).4B). The activation of TLR4 leads to the induction of IL-6 through the NF-��B signaling pathway [50]. Although CECs express low levels of TLR4 under normal conditions, the expression of TLR4 and IL-6 is increased in CECs from patients with UC, as well as in leukocytes and ECs [12], [51], suggesting that intestinal ECs may produce IL-6 through TLR4 expression during inflammation [52]. Our results provide supporting evidence for the crucial role of IL-6 in the generation of colonic inflammation, as IL-6 blockade delayed disease onset and attenuated colitis-associated symptoms in DSS-treated mice (Fig.

2A). This finding is consistent with Atreya et al. [13], who demonstrated that the blockade of IL-6 trans-signaling suppressed T-cell resistance to apoptosis in intestinal inflammation. Collectively, IL-6 elicits colonic inflammation in various ways, such as by stimulating innate immune organs (i.e., epithelial barrier), inducing the differentiation of adoptive immune cells (i.e., Th17 cells), and enhancing T-cell survival. This evidence provides insight into IL-6 function in multiple steps of UC generation and suggests a rationale for therapeutic approaches using IL-6 blockades, which could be effective treatment modalities for patients with UC. However, IL-6 has a protective effect on enterocytes and IECs [14], [17], [53].

In the development of colitis-associated cancer (CAC), the IL-6/STAT3 axis acts as an oncogenic signal cascade in CECs by promoting BCL-XL and cyclin D [14]. In addition, it has been known that patients with active UC had significantly more IL6 and p-STAT3-positive epithelial cells than both patients with inactive UC and controls [53]. Notably, mice lacking IL-6 (IL-6 null) or STAT3 in IECs show reduced CAC tumorigenesis but develop more severe DSS-induced colitis, with pronounced colonic ulceration and body weight loss, than do wild-type counterparts [14]. Tebbutt et al. [54] also showed that IL-6 null mice or those harboring the reciprocal mutation ablating STAT1/3 signaling show impaired colonic mucosal wound healing after DSS administration.

There are several possible explanations for the difference between our findings and the results of previous studies of the blockade of IL-6 signaling or STAT3 activation. It could stem from the use of knockout mice, the administration of the soluble receptor blocker Carfilzomib (sgp130Fc), or different methods of targeting the S100A9 molecule. In intestinal inflammation, S100A9 is an effector molecule that enhances TLR signaling [35] and recruits granulocytes [21], [22], [38], [47]. Thus, the blockade of this molecule can ameliorate disease severity in DSS-induced colitis (Fig. 5A�CC).