Importance of the alternative NF-κB activation pathway in inflammation-associated gastrointestinal carcinogenesis

Chronic inflammation is a common factor in the development of many gastrointestinal malignancies. Examples include inflammatory bowel disease predisposing to colorectal cancer, Barrett's esophagus as a precursor of esophageal adenocarcinoma, and Helicobacter pylori-induced gastric cancer. The classical activation pathway of NF-κB signaling has been identified as regulating several sporadic and inflammation-associated gastrointestinal tract malignancies. Emerging evidence suggests that the alternative NF-κB signaling pathway also exerts a distinct influence on these processes. This review brings together current knowledge of the role of the alternative NF-κB signaling pathway in the gastrointestinal tract, with a particular emphasis on inflammation-associated cancer development. members of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) family were initially described as transcription factors in B lymphocytes in 1986 (68). Since then, they have been shown to be widely expressed and are conserved across both vertebrates and invertebrates (5, 27). The conventional model of NF-κB signaling proposes two main arms of the pathway. These share similar features but are triggered independently and activate different target genes (76). The classical (canonical) NF-κB activation pathway is triggered by Th1 cytokines and is typified by the action of reticuloendotheliosis viral oncogene homolog A (RelA) (p65)-NF-κB1(p50) heterodimers, whereas the alternative (noncanonical) activation pathway signals through the adaptor protein NF-κB-inducing kinase (NIK). Activation of this mechanism leads to nuclear translocation of transcriptionally active v-rel avian reticuloendotheliosis viral oncogene homolog B (RelB)-NF-κB2(p52) heterodimers. Signaling through either pathway can influence multiple different cellular functions and can exert effects that may appear contradictory. For example, both pro- and anti-apoptotic effects, as well as proliferation (18) and senescence (70) signals, have been attributed to the classical activation pathway of NF-κB signaling. Because of the wide variation in outcomes following pathway activation, it is difficult to extrapolate the effects of NF-κB signaling from one context to another. Classical pathway NF-κB signaling has been identified as a key regulator of inflammation-associated carcinogenesis in several tissues since the early 2000s when Greten et al. demonstrated increased sensitivity to colitis-associated carcinogenesis in mice lacking IKK-β in intestinal epithelial cells (31), and, almost simultaneously Pikarsky et al. identified a similar increase in tumor burden in Mdr2 mice lacking IKK-β in hepatocytes (60). More recent evidence has established that alternative activation pathway NF-κB signaling is also important during the development of several gastrointestinal pathologies in mouse and humans. This article seeks to review this evidence and to establish questions for future research

On the Action of 5-Amino-Salicylic Acid and Sulfapyridine on M. avium including Subspecies paratuberculosis

BACKGROUND: Introduced in 1942, sulfasalazine (a conjugate of 5-aminosalicylic acid (5-ASA) and sulfapyridine) is the most prescribed medication used to treat "inflammatory" bowel disease (IBD.) Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We have shown that two other agents used in the therapy of IBD (methotrexate and 6-MP) profoundly inhibit MAP growth. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. We herein hypothesize that the mechanism of action of 5-ASA and/or sulfapyridine may also simply be to inhibit MAP growth. METHODOLOGY: The effect on MAP growth kinetics by sulfasalazine and its components were evaluated in bacterial culture of two strains each of MAP and M. avium, using a radiometric ((14)CO(2) BACTEC(R)) detection system that quantifies mycobacterial growth as arbitrary "growth index units" (GI). Efficacy data are presented as "percent decrease in cumulative GI" (%-DeltacGI). PRINCIPAL FINDINGS: There are disparate responses to 5-ASA and sulfapyridine in the two subspecies. Against MAP, 5-ASA is inhibitory in a dose-dependent manner (MAP ATCC 19698 46%-DeltacGI at 64 microg/ml), whereas sulfapyridine has virtually no effect. In contrast, against M. avium ATCC 25291, 5-ASA has no effect, whereas sulfapyridine (88%-DeltacGI at 4 microg/ml) is as effective as methotrexate, our positive control (88%-DeltacGI at 4 microg/ml). CONCLUSIONS: 5-ASA inhibits MAP growth in culture. We posit that, unknowingly, the medical profession has been treating MAP infections since sulfasalazine's introduction in 1942. These observations may explain, in part, why MAP has not previously been identified as a human pathogen. We conclude that henceforth in clinical trials evaluating antiMAP agents in IBD, if considered ethical, the use of 5-ASA (as well as methotrexate and 6-MP) should be excluded from control groups