Overexpression of interleukin-1bet ... | Article | H1 Connect

This article elegantly demonstrates that IL-1beta (IL-1B) per se is sufficient to induce gastric carcinogenesis in vivo. Previous studies have demonstrated that persons harboring high-expression alleles of IL-1B have an increased risk for gastric cancer if they are also infected with Helicobacter pylori. This group now demonstrates that over-expression of IL-1B within parietal cells in mice leads to pre-malignant and malignant lesions in the stomach. They further show that concomitant infection with Helicobacter accelerates the carcinogenic process, and they use novel in vitro and in vivo techniques to implicate NF-kB as the key signaling cascade regulating this process. Finally, they demonstrate that the carcinogenic process in this model is dependent upon myeloid derived suppressor cells, which builds upon their previous work defining a role for bone marrow derived stem cells in malignant transformation in the stomach. This important work will need to be reproduced in other models of gastric cancer but has provided novel and critical insights into how carcinomas arise from inflammatory foci.

This manuscript demonstrates that a single cytokine (interleukin 1 beta, IL-1B) is sufficient to induce gastric neoplasia in a mouse model and suggests that cytokine inhibition may be of therapeutic value in gastric cancer. Epidemiological evidence links pro-inflammatory polymorphisms in IL-1B with Helicobacter-induced gastric adenocarcinoma in Western populations {1}, and Houghton et al. previously demonstrated that bone marrow-derived inflammatory cells recruited by Helicobacter into the mouse stomach may themselves become the cells of origin of gastric neoplasia {2}. This study by Tu and colleagues links and advances these previous observations by demonstrating that stomach-specific overexpression of human IL-1B in transgenic mice induces gastric neoplasia even in the absence of Helicobacter infection. However, Helicobacter felis infection was found to increase the severity of the inflammation and accelerated neoplasia development in this model. The induction of gastric neoplasia by IL-1B was independent of lymphocytes but apparently due to the involvement of activated myeloid-derived suppressor cells (MDSCs), through the promotion of inflammatory cytokine and chemokine production via NFkB activation. Antagonism of IL-1 receptor signaling inhibited preneoplasia as well as MDSC mobilization, further corroborating the direct relationship between IL-1B and MDSCs. Myeloid-derived ‘inflammatory’ rather than ‘suppressor’ cells may be a better terminology according to this report. Interestingly, higher rates of dysplasia and adenocarcinoma and higher levels of inflammatory cytokines as well as MDSCs were observed in the male mice compared to their female counterparts “consistent with the unexplained male gender bias of gastric cancer in humans”. As noted by the authors, other downstream targets of IL-1B aside from MDSCs may also be contributing to the inflammatory process. Like all important work, this study raises as many questions as it does answers in the rapidly evolving field of inflammation-associated neoplasia, but the therapeutic implications regarding cytokine inhibition are exciting.