The proto-oncoprotein Bcl-3 is a member of the IkB family and is present predominantly in the nucleus. To gain insight into speci®c nuclear functions of Bcl-3 we have isolated proteins that interact with its ankyrin repeat domain. Using the yeast two-hybrid-system we identi®ed four novel binding partners of Bcl-3 in addition to NF-kB p50 and p52, previously known to associate with Bcl-3. The novel Bcl-3 interactors Jab1, Pirin, Tip60 and Bard1 are nuclear proteins which also bind to other transcription factors including c-Jun, nuclear factor I (NFI), HIV-1 Tat or the tumor suppressor and Polll holoenzyme component Brca1, respectively. Bcl-3, p50, and either Bard1, Tip60 or Pirin are sequestered into quarternary complexes on NF-kB DNA binding sites, whereas Jab1 enhances p50-Bcl-3-DNA complex formation. Furthermore, the histone acetylase Tip60 enhances Bcl-3-p50 activated transcription through an NF-kB binding site, indicating that quarternary complexes containing Bcl-3 interactors modulate NF-kB driven gene expression. These data implicate Bcl-3 as an adaptor between NF-kB p50/p52 and other transcription regulators and suggest that its gene activation function may at least in part be due to recruitment of the Tip60 histone actetylase.
To release transcription factor NF-B into the nucleus, the mammalian IB molecules IB␣ and IB are inactivated by phosphorylation and proteolytic degradation. Both proteins contain conserved signal-responsive phosphorylation sites and have conserved ankyrin repeats. To confer specific physiological functions to members of the NF-B/Rel family, the different IB molecules could vary in their specific NF-B/Rel factor binding activities and could respond differently to activation signals. We have demonstrated that both mechanisms apply to differential regulation of NF-B function by IB relative to IB␣. Via alternative RNA processing, human IB gives rise to different protein isoforms. IB1 and IB2, the major forms in human cells, differ in their carboxy-terminal PEST sequences. IB2 is the most abundant species in a number of human cell lines tested, whereas IB1 is the only form detected in murine cells. These isoforms are indistinguishable in their binding preferences to cellular NF-B/Rel homo-and heterodimers, which are distinct from those of IB␣, and both are constitutively phosphorylated. In unstimulated B cells, however, IB1, but not IB2, is found in the nucleus. Furthermore, the two forms differ markedly in their efficiency of proteolytic degradation after stimulation with several inducing agents tested. While IB1 is nearly as responsive as IB␣, indicative of a shared activation mechanism, IB2 is only weakly degraded and often not responsive at all. Alternative splicing of the IB pre-mRNA may thus provide a means to selectively control the amount of IB-bound NF-B heteromers to be released under NF-B stimulating conditions.Transcriptional induction of genes driven by members of the NF-B/Rel family of activators plays a crucial role in many processes of the immune response and under a number of cellular stress conditions including viral infection (2,5,40,44). The activation of NF-B through different pathways is controlled primarily by its release from the interaction with inhibitory IB molecules. Five different mammalian NF-B/Rel proteins are known, p50, p52, p65, c-Rel, and RelB, which form homo-and heterodimers. These are sequestered by the IB molecules IB␣, IB, and IBε and by p105 and p100, the precursor molecules for p50 and p52, respectively (2, 42). Best understood is the activation of NF-B from complexes with IB␣ by diverse inducers like tumor necrosis factor alpha (TNF-␣), lipopolysaccharide (LPS), phorbol myristate acetate, (PMA) or human T-cell leukemia virus type 1 Tax (7,8,38,43). These lead to phosphorylation at Ser 32 and 36. Phosphorylated IB␣ is then polyubiquitinated and subsequently degraded by the proteasome (3, 9, 34). In addition to the aminoterminal signal response box containing Ser 32 and 36, signaldependent degradation is more efficient in the presence of the carboxy-terminal PEST sequence of IB␣ (7,8,38,43), although the mechanistic need of the latter is not understood. The high turnover of IB␣ in the resting state is also driven by the proteasome but is independent of the amino-...
IntroductionPatients with rheumatoid arthritis (RA) treated with abatacept (ABT) are at increased risk for vaccine-preventable infections. The aim of the present study is to evaluate the humoral response to 23-valent pneumococcal polysaccharide (PPSV23) vaccination in RA patients receiving ABT.MethodsThe immunogenicity study was nested within a randomized, double-blind placebo-controlled study, designed to evaluate the efficacy of the PPSV23. PPSV23 was given to 111 RA patients, who were classified into three groups: RA control (n = 35), methotrexate (MTX) alone (n = 55), and ABT (n = 21). Before and 4–6 weeks after vaccination, we measured the patients’ concentrations of antibodies against pneumococcal serotypes 6B and 23F using an enzyme-linked immunosorbent assay and determined their antibody functionality using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI).ResultsThe pneumococcal serotype-specific IgG concentrations and OIs were both significantly increased in all treatment groups in response to PPSV23 vaccination. In the ABT group, the IgG responses for the 6B serotype were lower compared with those in the MTX alone or control groups, whereas the OI responses were similar to those in the other two groups. In a subgroup analysis, the pneumococcal serotype-specific IgG responses were significantly lower in both serotypes (6B and 23F) in the ABT/MTX group; however, the OI responses in the ABT group were not different from the control group. There was no association between the pneumococcal serotype-specific IgG and OI responses for the 6B serotype in patients receiving ABT in contrast to the control or MTX alone patients. No severe adverse effects were observed in any of the treatment groups.ConclusionsOI responses indicate antibody functionality rather than simply their amount, so the similarity of these measurements between all three groups suggests that RA patients receiving ABT still benefit from receiving the PPSV23 vaccination, even though they produce less IgG in response to it. The results suggest an influence of ABT on the humoral response to PPSV23 vaccination under MTX treatment; however, preserved opsonin responses are expected in RA patients treated with ABT plus MTX.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012.
IntroductionIn rheumatoid arthritis (RA) patients receiving immunosuppressive treatments, vaccination against Streptococcus pneumoniae is recommended. The objective of the study was to evaluate the effects of tacrolimus (TAC) on immune response following administration of a 23-valent pneumococcal polysaccharide vaccine (PPSV23) in patients with established RA.MethodsPatients with RA (n = 133) were vaccinated with PPSV23. Patients were classified into TAC (n = 29), methotrexate (MTX) (n = 55), control (n = 35), and TAC/MTX (n = 14) treatment groups. We measured the concentrations of pneumococcal serotypes 6B and 23F by using an enzyme-linked immunosorbent assay and determined antibody functionality by using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI), before and 4 to 6 weeks after vaccination. A positive antibody response was defined as at least a twofold increase in the IgG concentration or as at least a 10-fold increase in the OI.ResultsIgG concentrations and OIs were significantly increased in all treatment groups after PPSV23 vaccination. The TAC treatment group appears to respond in a manner similar to that of the RA control group in terms of 6B and 23F serotype concentration and function. In contrast, the MTX group had the lowest immune response. Patients who received a combination of TAC and MTX (TAC/MTX) also had a diminished immune response compared with those who received TAC alone.ConclusionsTAC monotherapy does not appear to impair PPSV23 immunogenicity in patients with RA, whereas antibody production and function may be reduced when TAC is used with MTX. Thus, PPSV23 administration during ongoing TAC treatment should be encouraged for infection-prone TAC-treated patients with rheumatic diseases.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0662-x) contains supplementary material, which is available to authorized users.
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