No abstract

The IκB kinase (IKK) complex is composed of three subunits, IKKα, IKKβ, and IKKγ (NEMO). While IKKα and IKKβ are highly similar catalytic subunits, both capable of IκB phosphorylation in vitro, IKKγ is a regulatory subunit. Previous biochemical and genetic analyses have indicated that despite their similar structures and in vitro kinase activities, IKKα and IKKβ have distinct functions. Surprisingly, disruption of the Ikkα locus did not abolish activation of IKK by proinflammatory stimuli and resulted in only a small decrease in nuclear factor (NF)-κB activation. Now we describe the pathophysiological consequence of disruption of the Ikkβ locus. IKKβ-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a phenotype that is remarkably similar to that of mice deficient in both the RelA (p65) and NF-κB1 (p50/p105) subunits of NF-κB. Accordingly, IKKβ-deficient cells are defective in activation of IKK and NF-κB in response to either tumor necrosis factor α or interleukin 1. Thus IKKβ, but not IKKα, plays the major role in IKK activation and induction of NF-κB activity. In the absence of IKKβ, IKKα is unresponsive to IKK activators.

Recent advances in the treatment of multiple myeloma (MM) have increased the need for accurate diagnosis of the disease. The detection of bone and bone marrow lesions is crucial in the work-up of MM, and often dictates the decision to start treatment. Furthermore, detection of minimal residual disease (MRD) is important for prognosis and treatment planning, and has underscored an unmet need for sensitive imaging modalities that accurately assess response to therapy in MM. Low dose whole body computed tomography (WBCT) has increased sensitivity compared to conventional skeletal survey (CSS) in the detection of bone disease, and can reveal information leading to changes in therapy and management that could prevent or delay the onset of significant morbidity and mortality related to skeletal-related events. Given the multiple options for detection of bone and bone marrow lesions ranging from CSS to WBCT, positron emission tomography (PET)-CT, and magnetic resonance imaging (MRI), the International Myeloma Working Group has established guidelines on the optimal and standardized use of imaging modalities in different stages of the disease. These recommendations on imaging within and outside of clinical trials will help to standardize the imaging worldwide in order to allow comparison of results and unification of treatment approaches.

Tumor necrosis factor (TNF) is a critical cytokine, which contributes to both physiological and pathological processes. This mini-review will briefly touch the history of TNF discovery, its family members and its biological and pathological functions. Then, it will focus on new findings on the molecular mechanisms of how TNF triggers activation of the NF-κB and AP-1 pathways, which are critical for expression of proinflammatory cytokines, as well as the MLKL cascade, which is critical for the generation of ROS in response to TNF. Finally, this review will briefly summarize recent advances in understanding TNF-induced cell survival, apoptosis and necrosis (also called necroptosis). Understanding new findings and emerging concepts will impact future research on the molecular mechanisms of TNF signaling in immune disorders and cancer-related inflammation.