Inflammatory bowel disease: past, present, and future

Crohn’s disease and ulcerative colitis, collectively known as the inflammatory bowel diseases (IBD), are largely diseases of the twentieth century, and are associated with the rise of modern, Westernized industrial society. Although the causes of these diseases remain incompletely understood, the prevailing model is that the intestinal flora drives an unmitigated intestinal immune response and inflammation in the genetically susceptible host. A review of the past and present of these diseases shows that detailed description preceded more fundamental elucidation of the disease processes. Working out the details of disease pathogenesis, in turn, has yielded dividends in more focused and effective therapy for IBD. This article highlights the key descriptions of the past, and the pivotal findings of current studies in disease pathogenesis and its connection to medical therapy. Future directions in the IBD will likely explicate the inhomogeneous causes of these diseases, with implications for individualized therapy

IL-1β Processing in Host Defense: Beyond the Inflammasomes

Stimulation and release of proinflammatory cytokines is an essential step for the activation of an effective innate host defense, and subsequently for the modulation of adaptive immune responses. Interleukin-1β (IL-1β) and IL-18 are important proinflammatory cytokines that on the one hand activate monocytes, macropages, and neutrophils, and on the other hand induce Th1 and Th17 adaptive cellular responses. They are secreted as inactive precursors, and the processing of pro-IL-1β and pro-IL-18 depends on cleavage by proteases. One of the most important of these enzymes is caspase-1, which in turn is activated by several protein platforms called the inflammasomes. Inflammasome activation differs in various cell types, and knock-out mice defective in either caspase-1 or inflammasome components have an increased susceptibility to several types of infections. However, in other infections and in models of sterile inflammation, caspase-1 seems to be less important, and alternative mechanisms such as neutrophil-derived serine proteases or proteases released from microbial pathogens can process and activate IL-1β. In conclusion, IL-1β/IL-18 processing during infection is a complex process in which the inflammasomes are only one of several activation mechanisms

Forced subduction initiation recorded in the sole and crust of the Semail Ophiolite of Oman

Subduction zones are unique to Earth and fundamental in its evolution, yet we still know little about the causes and mechanisms of their initiation. Numerical models show that far-field forcing may cause subduction initiation at weak pre-existing structures, while inferences from modern subduction zones suggest initiation through spontaneous lithospheric gravitational collapse. For both endmembers, the timing of subduction inception corresponds with initial lower plate burial, whereas coeval or delayed extension in the upper plate are diagnostic of spontaneous or forced subduction initiation, respectively. In modern systems, the earliest extension-related upper plate rocks are found in forearcs, but lower plate rocks that recorded initial burial have been subducted and are inaccessible. Here, we investigate a fossil system, the archetypal Semail Ophiolite of Oman, which exposes both lower and upper plate relics of incipient subduction stages. We show with Lu–Hf and U–Pb geochronology of the lower and upper plate material that initial burial of the lower plate occurred before 104 million years ago, predating upper plate extension and the formation of Semail oceanic crust by at least 8 Myr. Such a time lag reveals far-field forced subduction initiation and provides unequivocal, direct evidence for a subduction initiation mechanism in the geological record