ABSTRACT
Upon ligand binding, RIPK1 is recruited to tumor necrosis factor receptor superfamily (TNFRSF) and Toll-like receptor (TLR) complexes promoting prosurvival and inflammatory signaling. RIPK1 also directly regulates caspase-8-mediated apoptosis or, if caspase-8 activity is blocked, RIPK3-MLKL-dependent necroptosis. We show that C57BL/6 Ripk1(-/-) mice die at birth of systemic inflammation that was not transferable by the hematopoietic compartment. However, Ripk1(-/-) progenitors failed to engraft lethally irradiated hosts properly. Blocking TNF reversed this defect in emergency hematopoiesis but, surprisingly, Tnfr1 deficiency did not prevent inflammation in Ripk1(-/-) neonates. Deletion of Ripk3 or Mlkl, but not Casp8, prevented extracellular release of the necroptotic DAMP, IL-33, and reduced Myd88-dependent inflammation. Reduced inflammation in the Ripk1(-/-)Ripk3(-/-), Ripk1(-/-)Mlkl(-/-), and Ripk1(-/-)Myd88(-/-) mice prevented neonatal lethality, but only Ripk1(-/-)Ripk3(-/-)Casp8(-/-) mice survived past weaning. These results reveal a key function for RIPK1 in inhibiting necroptosis and, thereby, a role in limiting, not only promoting, inflammation.
Subject(s)
Genes, Lethal , Hematopoiesis , Inflammation/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Animals , Animals, Newborn , Caspase 8/metabolism , Cell Death , Liver/metabolism , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Protein Kinases/genetics , Protein Kinases/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Receptors, Tumor Necrosis Factor, Type I/metabolism , Tumor Necrosis Factors/metabolismABSTRACT
RIPK1 is involved in signaling from TNF and TLR family receptors. After receptor ligation, RIPK1 not only modulates activation of both canonical and NIK-dependent NF-κB, but also regulates caspase-8 activation and cell death. Although overexpression of RIPK1 can cause caspase-8-dependent cell death, when RIPK1(-/-) cells are exposed to TNF and low doses of cycloheximide, they die more readily than wild-type cells, indicating RIPK1 has pro-survival as well as pro-apoptotic activities. To determine how RIPK1 promotes cell survival, we compared wild-type and RIPK1(-/-) cells treated with TNF. Although TRAF2 levels remained constant in TNF-treated wild-type cells, TNF stimulation of RIPK1(-/-) cells caused TRAF2 and cIAP1 to be rapidly degraded by the proteasome, which led to an increase in NIK levels. This resulted in processing of p100 NF-κB2 to p52, a decrease in levels of cFLIP(L), and activation of caspase-8, culminating in cell death. Therefore, the pro-survival effect of RIPK1 is mediated by stabilization of TRAF2 and cIAP1.
Subject(s)
Caspase 8/metabolism , Inhibitor of Apoptosis Proteins/metabolism , NF-kappa B/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , TNF Receptor-Associated Factor 2/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Caspase 8/genetics , Cell Death/drug effects , Cell Death/physiology , Cell Survival/drug effects , Cell Survival/physiology , Cycloheximide/pharmacology , Enzyme Activation/drug effects , Enzyme Activation/physiology , Inhibitor of Apoptosis Proteins/genetics , Mice , Mice, Knockout , NF-kappa B/genetics , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Protein Stability , Protein Synthesis Inhibitors/pharmacology , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , TNF Receptor-Associated Factor 2/genetics , Tumor Necrosis Factor-alpha/pharmacology , NF-kappaB-Inducing KinaseABSTRACT
OBJECTIVE: The aim of the study was to document the response of patients to multiple impulse therapy for a variety of musculoskeletal complaints encountered in clinical practice. METHODS: A single practitioner in a private clinic setting provided the therapy to 249 patients. Survival analysis was used to plot probability of pain vs the days required for symptom resolution for each of 8 patient complaints. Analysis of variance was used to examine the influence of covariates such as age, sex, body mass index, and chronicity. RESULTS: The average number of visits required to achieve a pain-free state for each of 8 patient symptoms, the half-life for response to multiple impulse therapy, and comparison of the results of published studies of low back and neck pain are presented. CONCLUSION: Response of patients in the study sample to multiple impulse therapy for symptoms of low back and neck pain appeared to be considerably faster than that obtained in 3 recent studies.
Subject(s)
Musculoskeletal Diseases/therapy , Musculoskeletal Manipulations , Adolescent , Adult , Child , Female , Humans , Male , Middle Aged , Musculoskeletal Diseases/physiopathology , Neck Pain/physiopathology , Neck Pain/therapy , Pain/physiopathology , Survival Analysis , Treatment OutcomeABSTRACT
OBJECTIVE: To investigate patient response to multiple impulse therapy provided by the PulStarFRAS (Sense Technology, Inc, Murrysville, Pa) for a variety of musculoskeletal symptoms encountered in clinical practice. METHODS: A retrospective analysis of patient files was used to determine symptomatic improvement over the course of treatment. The multiple impulse therapy was supplemented, at the discretion of the practitioner, with manual adjustments. The manual adjustments consisted of high-velocity low-amplitude and drop table, and represented fewer than 5% of the adjustments. Therapy was provided by a single practitioner in a private clinic setting. RESULTS: Patients expressed improvement in symptoms after the first visit (average improvement in subjective pain rating scale of 41%). Patient symptoms improved between the first and second visits for 70% of patients (average improvement in subjective pain scale for all patients was 58%). The majority of patients achieved complete resolution of symptoms between the third and fourth visits. Maximum benefit for patients across all symptoms required an average of 4.2 visits. The half-life for response to multiple impulse therapy for all symptoms was 17 to 26 days. The half-life for response to multiple impulse therapy using the PulStarFRAS for low back pain was 9 to 16 days. CONCLUSION: The results of this study suggest the further study of multiple impulse therapy provided by the PulStarFRAS as a means of resolving musculoskeletal complaints.
Subject(s)
Musculoskeletal Diseases/therapy , Physical Therapy Modalities , Adolescent , Adult , Aged , Child , Female , Humans , Low Back Pain/therapy , Male , Middle Aged , Musculoskeletal Diseases/physiopathology , Neck Pain/therapy , Pain Measurement , Pilot Projects , Retrospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
OBJECTIVE: To present a new theoretical construct, the Minimum Energy Hypothesis, which explains structural changes observed in the spine concomitant to spinal joint fixation resolution in initial investigations. DESIGN: Theoretical analysis. HYPOTHESIS: A unified theory of manipulative effectiveness is proposed that integrates the fixation and sensory tonus models of manipulation. The theory is based on the fact that the spine will assume a position of minimum internal energy when mechanical equilibrium is achieved. By using a simple mathematical model, it is shown that the fixation model and the sensory tonus models are 2 different aspects of the same theoretical construct. The Minimum Energy Hypothesis predicts that the spine will seek an optimal minimum energy configuration if the constraints preventing it from doing so are removed. Constraints are hypothesized to be joint fixations caused by inflammation in and about the spine and its sequella, muscle spasm, fibroadipose and scar tissue, and ultimately, degeneration. It is further hypothesized that the use of a computerized mechanical manipulative device may resolve such fixations, an example of which is radiographically demonstrable cervical hypolordosis. CONCLUSION: A unified theory of manipulative effectiveness based on the concept of minimum energy to attain mechanical equilibrium is brought forward to explain the results of initial investigations.
