Distinct Mechanisms for Induction and Tolerance Regulate the Immediate Early Genes Encoding Interleukin 1β and Tumor Necrosis Factor α

Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. © 2013 Adamik et al

Sports-Related Injuries of the Anterior Segment

Sports-related eye injury is a significant cause of morbidity and disability and accounts for a significant proportion of ocular trauma, especially in the young. Although some sports-related ocular injuries can be self-resolving and require little to no intervention, many other injuries have long-term sequelae that require extensive treatment and follow-up. A thorough evaluation of the mechanism of and circumstances surrounding the ocular injury is important to guide further management of the case. Blunt trauma has a significantly different pathophysiologic process compared to trauma by a sharp object, and the evaluation of the injury should be cognizant of the ocular trauma expected. The conjunctiva is most frequently involved in sports-related ocular injuries, and the nature of the conjunctival injury can often indicate involvement of other potential ocular structures. Examples of other anterior segment injuries that can result from sports-related ocular trauma include structural or functional damage to the cornea, iris injury leading to iris prolapse or laceration, ciliary body injury resulting in ciliary body detachment, lens injury resulting in cataract or subluxation/dislocation of the lens, and traumatic glaucoma. In this chapter, we provide a comprehensive review of the pathogenesis, clinical findings, treatment options, and prognosis of sports-related injuries of the anterior segment