This is a continuation of a long term project aimed at understanding the regulation and function of NF-?B signaling pathways in immunity and inflammation. Past achievements include elucidation of classical and alternative NF-?B signaling pathways and the mechanisms responsible for their activation. During the current project period we made several unexpected and rather surprising findings that are of great importance and we will pursue them during the next project period. Perhaps, the most surprising finding is the massive mucosal damage and intestinal epithelial cell (IEC) death caused by TNF administration to mice that express constitutively active IKK? in IEC. This finding seems contradictory to the well-established anti-apoptotic function of NF-?B in most cell types, including IEC, but preliminary studies confirm that the TNF-induced death of IEC that express constitutively active IKK? is distinct from the apoptotic cell death induced by TNF in NF-?B- deficient cells. We will investigate the mechanism responsible for this interesting phenomenon as it can explain how TNF causes damage of chronically inflamed tissues, while in normal, uninflammed, tissues, it actually provides a protective function. We expect these studies to advance the understanding of chronic inflammatory diseases, especially ulcerative colitis (UC) and Crohn's disease (CD). Another important function of NF-?B signaling is the production of key immunoregulatory cytokines, such as IL-23, in response to engagement of pattern recognition receptors (PRR). We found that IL-23 production is strongly elevated in tumor associated macrophages (TAM) of colorectal tumors relative to normal lamina propria macrophages. As the IL-23-IL-17 axis controls the progression of human and mouse colorectal cancers (CRC), we will study in detail the mechanisms that trigger its activation by identifying the PRRs responsible for tumoral IL-23 production and by investigating how colorectal tumors become permeable to TAM-activating microbial products. In this respect, we will investigate how loss of the APC tumor suppressor, NF-?B and STAT3 activation in pre-malignant IEC results in loss of junctional proteins and mucin expression, thereby contributing to barrier disruption. Similar mechanisms may underlie barrier deterioration in UC and CD, inflammatory bowel diseases that increase CRC risk. Our preliminary studies suggest that STAT3, whose activity is modulated by IKK?/NF-?B signaling, may be a key factor in the control of epithelial homeostasis. Our preliminary studies also revealed an unexpected link between STAT3 and YAP, a transcriptional co-activator that controls tissue growth and regeneration. We will investigate how STAT3 leads to YAP activation and whether YAP mediates the effects of STAT3 on mucosal homeostasis. We will also investigate the potential cross-talk between NF-?B and YAP, which is activated during experimental colitis to control mucosal regeneration and tumorigenesis. The proposed studies will be based on a combination of biochemistry, cell biology, and mouse physiology, an integrated approach that was proven very effective in the past.
We will investigate the roles of I?B kinase (IKK) and NF-?B and their interactions with STAT3 in the control of epithelial homeostasis, inflammation and immunity. The proposed studies will advance our understanding of chronic inflammatory diseases that lead to tissue destruction and colorectal tumorigenesis.
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|Sun, Beicheng; Karin, Michael (2014) The therapeutic value of targeting inflammation in gastrointestinal cancers. Trends Pharmacol Sci 35:349-57|
|Valeri, Nicola; Braconi, Chiara; Gasparini, Pierluigi et al. (2014) MicroRNA-135b promotes cancer progression by acting as a downstream effector of oncogenic pathways in colon cancer. Cancer Cell 25:469-83|
|Charlaftis, Nikolaos; Suddason, Tesha; Wu, Xuefeng et al. (2014) The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines. EMBO J 33:2581-96|
|Wang, Kepeng; Kim, Min Kyoung; Di Caro, Giuseppe et al. (2014) Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis. Immunity 41:1052-63|
|Li, Ning; Wu, Xuefeng; Holzer, Ryan G et al. (2013) Loss of acinar cell IKK* triggers spontaneous pancreatitis in mice. J Clin Invest 123:2231-43|
|Gukovsky, Ilya; Li, Ning; Todoric, Jelena et al. (2013) Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology 144:1199-209.e4|
|Mancino, Alessandra; Habbeddine, Mohamed; Johnson, Ella et al. (2013) I kappa B kinase alpha (IKKýý) activity is required for functional maturation of dendritic cells and acquired immunity to infection. EMBO J 32:816-28|
|Li, Ning; Grivennikov, Sergei I; Karin, Michael (2011) The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell 19:429-31|
|Hacker, Hans; Tseng, Ping-Hui; Karin, Michael (2011) Expanding TRAF function: TRAF3 as a tri-faced immune regulator. Nat Rev Immunol 11:457-68|
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