Persistent Cyclooxygenase-2 Inhibition Downregulates NF-κB, Resulting in Chronic Intestinal Inflammation in the Min/+ Mouse Model of Colon Tumorigenesis

Abstract

COX-2 inhibition prevents adenoma formation in humans and mouse models of colon cancer. The selective COX-2 inhibitor, celecoxib, reduces COX-2 and PGE2 expression and adenomas in the intestine of Min/+ mice after treatment for several weeks, but prolonged treatment increases PGE2 production, resulting in drug-resistant tumor formation and TGFβ-dependent intestinal fibrosis. In this study, we examined pathways that regulate COX-2 expression and suppress chronic intestinal inflammation. We show that NF-κB signaling was inhibited in the ileum of Min/+ mice receiving long-term treatment with celecoxib. This effect was associated with inhibition of TAK-1 and IKKα/β activities and reduced expression of the Toll-like receptors TLR2 and TLR4 that enhance colonic barrier function. Additionally, we observed reduced activities of protein kinases JNK1 and PKA and transcription factor CREB, regulators of COX-2 expression which crosstalk with NF-κB. In ileum subjected to long-term celecoxib treatment, we noted relatively higher expression of COX-2, VEGF, and IL-1β in Paneth cells, while NF-κB and COX-2 were more strongly expressed by an expanded population of stromal myofibroblasts. Our findings argue that celecoxib resistance is an acquired adaptation to changes in the crypt microenvironment that is associated with chronic intestinal inflammation and impaired acute wound-healing responsiveness.

A Novel Peroxisome Proliferator-activated Receptor (PPAR)γ Agonist 2-Hydroxyethyl 5-chloro-4,5-didehydrojasmonate Exerts Anti-Inflammatory Effects in Colitis

“…As previously mentioned, the NF-B pathway plays a central role in inflammation (16,17). Persistent COX-2 inhibition through long-term treatment of celecoxib down-regulates NF-B activity in enterocytes (29). Therefore, COX-2 inhibition by J11-C1 in inflamed colon tissues may contribute to NF-B inhibition.…”

Obesity-associated cancer risk: the role of intestinal microbiota in the etiology of the host proinflammatory state

“…Effectors of TLR4 activation are MyD88 and subsequently NFκB, which is a key signaling molecule for the inflammatory response and cytokine production (100, 106–110). The LPS/TLR4/NFκB pathway has been suggested to be a target for colon cancer prevention because of the central role of NFκB in cell proliferation, transformation and tumor progression (107–109). …”

Nadroparin Sodium Activates Nrf2/HO-1 Pathway in Acetic Acid-Induced Colitis in Rats

“…As HO-1 defensive system, cyclooxygenase-2 (COX-2) production has also been upregulated by redox-sensitive transcription factors at the sites of inflammation [24]. It has been demonstrated that downregulation of COX-2 eventuates in reducing intestinal inflammation [25][26][27] and also leading to amelioration of the colitis [28,29]. In the present study, we aimed to evaluate the effects of nadroparin calcium, a LMWH, treatment on HO-1 expression, and redox-sensitive transcription factors levels (AP-1, NF-κB, and Nrf2), COX-2, TNF-alpha, and IL-6 in acetic acid (AA)-induced colitis in rats.…”