A20, also referred to as tumor necrosis factor alpha (TNFα)-induced protein 3 (TNFAIP3), is an ubiquitin-editing enzyme whose expression is enhanced by NF-κB activation, and plays an important role in silencing NF-κB activity. Another well-known role for A20 is to protect cells from TNFα-induced apoptosis. Depletion of NF-κB in differentiating U937 monocytic leukemia cells is known to cause apoptotic cell death; however, much remains to be explored about the molecules that are expressed in an NF-κB-dependent manner and which support monocyte-macrophage differentiation. Using the monocytic cell line THP-1, and peripheral blood monocytes, we show here a sustained increase in A20 expression during monocyte-macrophage differentiation, which coincided with high NF-κB-dependent transcriptional activity. Depletion of NF-κB by stable expression of a super-repressor form of IκBα in THP-1 cells caused remarkable cell death during phorbol 12-myristate 13-acetate (PMA)-induced differentiation. A20 expression in these cells did not alter this NF-κB suppression, but was sufficient to protect the cells and restore the cell surface expression of a differentiation marker (CD11b) and phagocytic activity. Mutational analyses revealed that this A20 activity requires the carboxy-terminal zinc-finger domain, but not its deubiquitinase activity. Based on these findings, we conclude that A20, when ectopically expressed, can support both survival and differentiation of THP-1 cells in the absence of sustained NF-κB activity.

No abstract

Background and ObjectivesAlthough the importance of pediatric-to-adult health care transition (HCT) has been recognized, individuals with childhood-onset neurologic conditions often encounter challenges during pediatric-to-adult HCT, and HCT benefits for this population remain elusive. We assessed the current HCT situation in individuals with childhood-onset neurologic conditions to develop an improved transition system that incorporates patient perspectives.MethodsThis cross-sectional study was conducted at the Tokyo Metropolitan Kita Medical and Rehabilitation Center for the Disabled from November 2020 to December 2020. We targeted adults with childhood-onset neurologic conditions who visited the Department of Internal Medicine and their families. Questionnaires provided to 127 patients asked them about their experiences with pediatric-to-adult HCT (i.e., educational opportunities regarding HCT during pediatric visits, difficulties in transition, and the merits/demerits of adult practice) and their families' perspectives regarding pediatric-to-adult HCT. We also reviewed the patients' medical records to examine the severity of their disabilities.ResultsResponses were collected from 111 patients (response rate: 87%). Most patients had both severe physical and intellectual disabilities, and approximately half had a physical disability level of Gross Motor Function Classification System V and a profound intellectual disability. Half of the respondents were not transitioned through pediatric-to-adult HCT by their pediatricians, and they visited adult departments by themselves without a formal referral process. They experienced difficulties during HCT, such as a lack of knowledge regarding adult health care providers and consultants. However, those who underwent HCT benefited from it in terms of their health, experience, and service use, such as age- and condition-appropriate care, seeing adult specialists, and the introduction of adult services. They also addressed challenges in managing appointments and having adult doctors understand their medical history. Nonetheless, they were not informed about diseases and medical and welfare resources for adulthood during pediatric visits and desired to discuss future plans with pediatricians.DiscussionSystems that provide sufficient pediatric-to-adult HCT for individuals with childhood-onset neurologic conditions are required. Lifelong education for patients and families, training for pediatricians on HCT and neurologists on childhood-onset conditions and disabilities, and clinical practice and human resources that support patients and families are warranted.