The CARMA1-Bcl10 Signaling Complex Selectively Regulates JNK2 Kinase in the T Cell Receptor-Signaling Pathway

SummaryMembers of the c-Jun NH2-terminal kinase (JNK) family play crucial roles in cell activation, differentiation, and apoptosis. Although many studies have indicated that JNK1 and JNK2 have functional differences and redundancy, the upstream signaling pathway that selectively activates JNK1 or JNK2 remains unknown. In this study, we have revealed a selective mechanism of JNK activation, in which JNK2, but not JNK1, was regulated by CARMA1, a scaffold molecule, after stimulation of the T cell receptor (TCR). This CARMA1-dependent regulation of JNK2 worked through the scaffold molecule Bcl10, which was inducibly associated with JNK2 and served as a JNK-interacting protein (JIP)-like scaffold to assemble the kinases JNK2, MKK7, and TAK1. Finally, we showed that CARMA1- and Bcl10-mediated JNK2 activation had a critical role in regulating the amount of c-Jun protein. Together, our studies provide genetic evidence that JNK1 and JNK2 are differentially regulated in the TCR-signaling pathway and play different functions

TL1A–DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease

T helper type 17 (Th17) cells play an important pathogenic function in autoimmune diseases; their regulation, however, is not well understood. We show that the expression of a tumor necrosis factor receptor family member, death receptor 3 (DR3; also known as TNFRSF25), is selectively elevated in Th17 cells, and that TL1A, its cognate ligand, can promote the proliferation of effector Th17 cells. To further investigate the role of the TL1A–DR3 pathway in Th17 regulation, we generated a TL1A-deficient mouse and found that TL1A−/− dendritic cells exhibited a reduced capacity in supporting Th17 differentiation and proliferation. Consistent with these data, TL1A−/− animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE). Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells. These observations thus establish an important role of the TL1A–DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease

Phosphorylation and ubiquitination of the IκB kinase complex by two distinct signaling pathways

The IκB kinase (IKK) complex serves as the master regulator for the activation of NF-κB by various stimuli. It contains two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKKα/β at its activation loop and the K63-linked ubiquitination of NEMO. However, the molecular mechanism by which these inducible modifications occur remains undefined. Here, we demonstrate that CARMA1, a key scaffold molecule, is essential to regulate NEMO ubiquitination upon T-cell receptor (TCR) stimulation. However, the phosphorylation of IKKα/β activation loop is independent of CARMA1 or NEMO ubiquitination. Further, we provide evidence that TAK1 is activated and recruited to the synapses in a CARMA1-independent manner and mediate IKKα/β phosphorylation. Thus, our study provides the biochemical and genetic evidence that phosphorylation of IKKα/β and ubiquitination of NEMO are regulated by two distinct pathways upon TCR stimulation

The next generation of collaborative care: The design of a novel web-based stepped collaborative care intervention delivered via telemedicine for people diagnosed with cancer

The NIH consensus statement on cancer-related symptoms concluded the most common and debilitating were depression, pain and fatigue [1–6]. Although the comorbidity of these symptoms is well known and may have similar underlying biological mechanisms no intervention has been developed to reduce these symptoms concurrently. The novel web-based stepped collaborative care intervention delivered by telemedicine is the first to be tested in people diagnosed with cancer.We plan to test a web-based stepped collaborative care intervention with 450 cancer patients and 200 caregivers in the context of a randomized controlled trial. The primary endpoint is quality of life with other primary outcomes including patient-reported depression, pain, fatigue. Secondary outcomes include patient serum levels of pro-inflammatory cytokines and disease progression. We also will assess informal caregiver stress, depression, and metabolic abnormalities to determine if improvements in patients' symptoms also relate to improvement in caregiver outcomes.The trial is ongoing and a total of 382 patients have been randomized. Preliminary analyses of the screening tools used for study entry suggest that Center for Epidemiological Studies-Depression (CESD) scale has good sensitivity and specificity (0.81 and 0.813) whereas the scale used to assess pain (0.47 and 0.91) and fatigue (0.11 and 0.91) had poor sensitivity but excellent specificity. Using the AUROC, the best cut point for the CES-D was 19, for pain was 4.5; and for fatigue was 2.5. Outcomes not originally proposed included health care utilization and healthcare charges. The first 100 patients who have been followed a year post-treatment, and who were less than 75 years and randomized to the web-based stepped collaborative care intervention, had lower rates of complications after surgery [χ2 = 5.45, p = 0.02]. For patients who survived 6 months or less and were randomized to the web-based stepped collaborative care intervention, had lower rates of 90-day readmissions when compared to patients randomized to the screening and referral arm [χ2 = 4.0, p = 0.046]. Patients randomized to the collaborative care intervention arm had lower overall health care activity-based costs of $16,758 per patient per year when compared to the screening and referral arm.This novel web-based stepped stepped collaborative care intervention, delivered via telemedicine, is expected to provide a new strategy to improve the quality of life in those diagnosed with cancer and their caregivers.ClinicalTrials.govNCT0293975

The benefits and consequences of the COVID-19 pandemic for patients diagnosed with cancer and their family caregivers

The objectives of this study were to examine benefits and consequences of the COVID-19 pandemic for patients diagnosed with cancer and their family caregivers. A 23-item questionnaire assessing COVID-19-related issues, the Patient Health Questionnaire-2, Generalized Anxiety Disorder-2, Pittsburgh Sleep Quality Index, and the Perceived Stress Scale (PSS)-4 were administered to patients diagnosed with cancer and their family caregivers. Of the 161 patients and 78 caregivers who participated, 38.1% and 32.8 were male, 95% and 84.6% Caucasian, and the mean age was 66 and 64.6 years, respectively. A total of 16.5% and 15.2% reported depressive symptoms, 18.4% and 19% reported anxiety; 35.5% and 26.6% reported poor sleep quality, and 66% and 63.3% scored one standard deviation above the norms for the PSS, respectively. Predictors of poorer patient- and caregiver-reported outcomes included greater loneliness, worry about self or family being infected by the COVID-19, and worsening relationships with family. The fear of COVID-19 led to 20.8% of patients and 24.4% of family caregivers cancelling medical appointments, procedures, and treatments. A total of 52.5% of patients and 53.2% caregivers reported that the pandemic led to benefit finding but these changes were not associated with any of the measured patient- or caregiver-related outcomes. Psychological functioning for patients and caregivers was similar to that of pre-pandemic levels, however the decrease in health care utilization secondary to fear of COVID-19 was notable. While there were many negative effects of the pandemic, the majority of patients and caregivers reported some benefit to the pandemic

Naive OT-II cells were differentiated and DR3 expression was analyzed by real-time PCR analysis

DR3 expression was determined relative to naive CD4 T cell expression levels and normalized to GAPDH levels in all samples. (A) Comparison of DR3 expression on CD4 cells differentiated under Th1, Th2, and Th17 conditions. (B) Time-course analysis of DR3 expression in CD4 T cells differentiating under Th17 conditions. (C) Analysis of DR3 expression in cells differentiated under different combinations of cytokines. Primers used in A–C detect all DR3 isoforms. (D) Analysis of the full-length transmembrane-containing DR3 isoform (variant 1) in Th17 and T reg cells. (E) The ratio of total transmembrane DR3 (variants 1 and 3 combined) and full-length transmembrane DR3 (variant 1) was measured in Th17 and T reg cells. Error bars represent SD.<p><b>Copyright information:</b></p><p>Taken from "TL1A–DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease"</p><p></p><p>The Journal of Experimental Medicine 2008;205(5):1049-1062.</p><p>Published online 12 May 2008</p><p>PMCID:PMC2373838.</p><p></p

(A) In vitro–differentiated Th1 and Th17 cells were left unstimulated or restimulated on day 5 with WT or TL1A KO BMDCs for 24 h

Proliferation was measured by [H]thymidine incorporation during the last 8 h of stimulation. (B) In vitro–differentiated Th17 cells were stimulated with WT or TL1A KO BMDCs with and without Fc-TL1A for 24 h. Proliferation was measured by [H]thymidine incorporation during the last 8 h of stimulation. (C) In vitro–differentiated Th1 and Th17 cells were stimulated with WT or TL1A KO BMDCs pulsed with a titrating dose of OT-II peptide. The proliferation of Th1 and Th17 cells was determined at 24 h of stimulation by [H]thymidine incorporation. The horizontal dashed line represents the baseline proliferation of Th1 or Th17 cells alone. Data are representative of three independent experiments. Error bars represent SD.<p><b>Copyright information:</b></p><p>Taken from "TL1A–DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease"</p><p></p><p>The Journal of Experimental Medicine 2008;205(5):1049-1062.</p><p>Published online 12 May 2008</p><p>PMCID:PMC2373838.</p><p></p

Naive OT-II CD4 T cells were stimulated with either WT or TL1A KO BMDCs under polarized Th1- and Th17-differentiating conditions

Cells were harvested on day 6 and restimulated with PMA plus ionomycin, followed by intracellular cytokine staining for IFN-γ and IL-17. Dot plots represent the IFN-γ and IL-17 expression among CD4 cells (percentages are shown). Data are representative of three independent experiments.<p><b>Copyright information:</b></p><p>Taken from "TL1A–DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease"</p><p></p><p>The Journal of Experimental Medicine 2008;205(5):1049-1062.</p><p>Published online 12 May 2008</p><p>PMCID:PMC2373838.</p><p></p