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Spinal Manipulative Therapy Reduces Inflammatory Cytokines but Not Substance P Production in Normal Subjects
Abstract
To examine the effect of a single spinal manipulation therapy (SMT) on the in vitro production of inflammatory cytokines, tumor necrosis factor alpha, and interleukin (IL) 1beta, in relation to the systemic (in vivo) levels of neurotransmitter substance P (SP).
Sixty-four asymptomatic subjects were assigned to SMT, sham manipulation, or venipuncture control group. SMT subjects received a single adjustment in the thoracic spine. Blood and serum samples were obtained from subjects before and then at 20 minutes and 2 hours after intervention. Whole-blood cultures were activated with lipopolysaccharide (LPS) for 24 hours. Cytokine production in culture supernatants and serum SP levels were assessed by specific immunoassays.
Over the study period, a significant proportion (P </= .05) of sham and control subjects demonstrated progressive increases in the synthesis of tumor necrosis factor alpha and IL-1beta. Conversely, in a comparable proportion of cultures from SMT-derived subjects, the production of both cytokines decreased gradually. Normalization of the observed alterations to reflect the changes relative to self-baselines demonstrated that, within 2 hours after intervention, the production of both cytokines increased significantly (P < .001 to .05) in both controls. In contrast, a significant (P < .001 to .05) reduction of proinflammatory cytokine secretion was observed in cultures from SMT-receiving subjects. In all study groups, serum levels of SP remained unaltered within 2 hours after intervention.
SMT-treated subjects show a time-dependent attenuation of LPS-induced production of the inflammatory cytokines unrelated to systemic levels of SP. This suggests SMT-related down-regulation of inflammatory-type responses via a central yet unknown mechanism.
... Out of 15 studies [15,[18][19][20][21]35,36,[51][52][53][54][55][56][57][58], nine studies were RCTs with three groups [21,35,36,51,52,54,[56][57][58] five studies were RCTs with two groups [15,[18][19][20]55] and one study had four groups [53]. ...
... Out of 15 studies [15,[18][19][20][21]35,36,[51][52][53][54][55][56][57][58], nine studies were RCTs with three groups [21,35,36,51,52,54,[56][57][58] five studies were RCTs with two groups [15,[18][19][20]55] and one study had four groups [53]. ...
... The mean age of participants across all studies was 29.7 years. While 11 studies [15,20,21,35,51,[53][54][55][56][57][58] included both male and female participants; three studies [19,36,52] included only male participants; and one study [18] [18,20,53,58] included participants with pain (3 with neck pain and 1 with Achilles tendinopathy) and one study incuded participants with renal lithiasis. ...
Objective:
The aim of this systematic review was to update the current level of evidence for spinal manipulation in influencing various biochemical markers in healthy and/or symptomatic population.
Methods:
This is a systematic review update. Various databases were searched (inception till May 2023) and fifteen trials (737 participants) that met the inclusion criteria were included in the review. Two authors independently screened, extracted and assessed the risk of bias in included studies. Outcome measure data were synthesized using standard mean differences and meta-analysis for the primary outcome (biochemical markers). The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used for assessing the quality of the body of evidence for each outcome of interest.
Results:
There was low-quality evidence that spinal manipulation influenced various biochemical markers (not pooled). There was low-quality evidence of significant difference that spinal manipulation is better (SMD -0.42, 95% CI - 0.74 to -0.1) than control in eliciting changes in cortisol levels immediately after intervention. Low-quality evidence further indicated (not pooled) that spinal manipulation can influence inflammatory markers such as interleukins levels post-intervention. There was also very low-quality evidence that spinal manipulation does not influence substance-P, neurotensin, oxytocin, orexin-A, testosterone and epinephrine/nor-epinephrine.
Conclusion:
Spinal manipulation may influence inflammatory and cortisol post-intervention. However, the wider prediction intervals in most outcome measures point to the need for future research to clarify and establish the clinical relevance of these changes.
... These studies showed an association in time between in-vitro evoked-released reduced levels of CC motif chemokine ligand (CCL)-3, CCL-4, TNF-α, IL-6, soluble TNF receptor type (sTNFR)-2, ex-vivo serum hsCRP, and pain intensity in patients who received spinal mobilisations/manipulation 12,13,15 . However, the results of these studies have to be interpreted with caution as they used modest sample sizes 12,13,[15][16][17] , narrow selections of inflammatory markers 13 , lacked correction for potential confounding variables 12,13,[15][16][17] , did not investigate the associations between inflammatory markers and clinical outcome 12,13,[15][16][17] , or failed to use a placebo and randomised control group 12,13,[15][16][17] . ...
... These studies showed an association in time between in-vitro evoked-released reduced levels of CC motif chemokine ligand (CCL)-3, CCL-4, TNF-α, IL-6, soluble TNF receptor type (sTNFR)-2, ex-vivo serum hsCRP, and pain intensity in patients who received spinal mobilisations/manipulation 12,13,15 . However, the results of these studies have to be interpreted with caution as they used modest sample sizes 12,13,[15][16][17] , narrow selections of inflammatory markers 13 , lacked correction for potential confounding variables 12,13,[15][16][17] , did not investigate the associations between inflammatory markers and clinical outcome 12,13,[15][16][17] , or failed to use a placebo and randomised control group 12,13,[15][16][17] . ...
... These studies showed an association in time between in-vitro evoked-released reduced levels of CC motif chemokine ligand (CCL)-3, CCL-4, TNF-α, IL-6, soluble TNF receptor type (sTNFR)-2, ex-vivo serum hsCRP, and pain intensity in patients who received spinal mobilisations/manipulation 12,13,15 . However, the results of these studies have to be interpreted with caution as they used modest sample sizes 12,13,[15][16][17] , narrow selections of inflammatory markers 13 , lacked correction for potential confounding variables 12,13,[15][16][17] , did not investigate the associations between inflammatory markers and clinical outcome 12,13,[15][16][17] , or failed to use a placebo and randomised control group 12,13,[15][16][17] . ...
Abstract Spinal mobilisation/manipulation is a common intervention for spinal pain, yet the working mechanisms are largely unknown. A randomised placebo-controlled trial was conducted to (1) compare the immediate neuroimmune responses following spinal mobilisation/manipulation and placebo spinal mobilisation/manipulation; (2) compare the immediate neuroimmune responses of those with a good outcome with those of a poor outcome following spinal mobilisation/manipulation; and (3) explore the association between neuroimmune responses and pain reduction. One hundred patients were randomly allocated to spinal mobilisation/manipulation or a placebo mobilisation/manipulation. Primary outcomes were whole blood in-vitro evoked released concentrations of IL-1β and TNF-α measured 10 min and 2 h after the intervention. Immediate effects were studied because successful mobilisation/manipulation is often associated with immediate pain reduction, and immediate neuroimmune responses are less affected by potential confounders than long-term responses. Secondary outcomes included multiple systemic inflammatory marker concentrations, phenotypic analysis of white blood cells and clinical outcomes. Outcomes were compared between the experimental and placebo group, and between people with a good and poor outcome in the experimental group. Estimates of intervention effects were based on intention-to-treat analyses, by using linear mixed-effect models. Although there was a substantial difference in pain reduction between groups (mean (SD) difference visual analogue scale: 30 (21) mm at 10 min and 32 (21) mm at 2 h (p
... • нормализация/уменьшение пальпаторно и визуально определяемого мышечного тонуса [16,17]; • уменьшение мышечного тонуса и улучшение кровоснабжения мышц по данным вибрационной вискоэластометрии [18,19]; • увеличение объема движений в суставах конечностей [20,21]; • увеличение объема движений в спине и шее [22,23]; • увеличение ширины открывания рта [24]; • изменение плотности коллагеновых волокон и их ориентации в структуре матрикса, уменьшение количества поперечных сшивок в них, повышение гидратации матрикса [25,26]; • изменение качественного и количественного состава внеклеточного матрикса вследствие механически индуцированных изменений синтетической активности фибробластов [7,27]; • уменьшение уровня провоспалительных цитокинов и уменьшение периферической сенситизации [28][29][30][31]; • снижение активности симпатического отдела и повышение активности парасимпатического отдела вегетативной нервной системы, восстановление вегетативного равновесия по данным анализа вариабельности сердечного ритма [12,[32][33][34]; • повышение уровня окситоцина в плазме [35]; • снижение уровня психологического стресса, уровня кортизола в крови [36]; • повышение уровня β-эндорфинов, серотонина и эндогенных каннабиноидов [37,38]; • улучшение внешнего дыхания, увеличение жизненной ёмкости легких (ЖЁЛ) [39]; • нормализация венозного давления (исходно повышенное снижалось, исходно пониженное повышалось) [40]; • активация венозного возврата к сердцу за счет увеличения подвижности грудной клетки и присасывающего действия диафрагмы [41]; • нормализация венозного оттока от головы [16,42]; • улучшение кровотока по позвоночным артериям, уменьшение асимметрии кровотока по данным УЗДГ [17,[43][44][45]; • улучшение микроциркуляции за счет выхода вазоактивных веществ из клеток соединительной ткани (оксида азота, простагландинов, гистамина и др.) [46]; • улучшение лимфообразования и лимфотока [47,48]; • выход лейкоцитов из депо [49]; • уменьшение количества внеклеточной жидкости по данным биоимпедансометрии [50]; • уменьшение вязкости тканей по данным вибрационной вискоэластометрии [51]. Таким образом, эффекты ОК могут быть по степени выраженности локальными (в виде изменения коллоидного состояния, степени гидратации и структуры ткани, улучшения подвижности сустава, изменения локальной температуры), сегментарными (в виде рефлекторных изменений) или региональными (в виде улучшения кровоснабжения и лимфотока) и глобальными (в виде гормональных эффектов, изменения функционирования ЦНС). ...
The article describes the main objects of osteopathic influence in the body and the caused effects. The effects of osteopathic correction can occur at different times after the session and can be recorded using various clinical and instrumental methods. This should be taken into account when prescribing a re-examination of the patient to confirm the treatment results. A brief review of randomized controlled trials proving the efficacy of osteopathic correction in various diseases is also presented.
... Further, emerging data from animal and human studies support the hypothesis that SMT modulates the inflammatory response, influencing inflammatory cytokines. [25][26][27][28] Cytokines can induce neuroinflammation, which may mediate the development of CS 29 30 in the transition towards chronic pain. 8 31 SMT may thus relieve CLBP by impacting mechanisms linked to CS. 24 [32][33][34] Altered pain sensitivity in a specific musculoskeletal region may indicate nociplastic pain, 12 35 36 likely reflecting CS. 13 Abundant studies have reported that a subgroup of patients with CLBP demonstrate segmental mechanical hyperalgesia, assessed via lower pressure pain thresholds (PPTs) in low back or lower extremity areas, when compared with healthy controls. ...
Introduction
Chronic low back pain (CLBP) is a highly prevalent and disabling condition. Identifying subgroups of patients afflicted with CLBP is a current research priority, for which a classification system based on pain mechanisms was proposed. Spinal manipulative therapy (SMT) is recommended for the management of CLBP. Yet, little data are available regarding its mechanisms of action, making it difficult to match this intervention to the patients who may benefit the most. It was suggested that SMT may influence mechanisms associated with central sensitisation. Therefore, classifying patients with CLBP according to central sensitisation mechanisms may help predict their response to SMT.
Methods and analysis
This protocol describes a randomised placebo-controlled trial aiming to examine which variables linked to central sensitisation may help predict the clinical response to SMT in a cohort of patients with CLBP. One hundred patients with chronic primary low back pain will be randomised to receive 12 sessions of SMT or placebo SMT over a 4-week period. Pain intensity and disability will be assessed as primary outcomes after completing the 4-week treatment (primary endpoint), and at 4-week and 12-week follow-ups. Baseline values of two pain questionnaires, lumbar pressure pain thresholds, concentrations of an inflammatory cytokine and expectations of pain relief will be entered as predictors of the response to SMT in a multiple regression model. Changes in these variables after treatment will be used in a second multiple regression model. The reference values of these predictors will be measured from 50 age and sex-matched healthy controls to allow interpretation of values in patients. Mixed analyses of variance will also be conducted to compare the primary outcomes and the predictors between groups (SMT vs placebo) over time (baseline vs post-treatment).
Ethics and dissemination
Ethical approval was granted by the Fundación Jiménez Díaz Clinical Research Ethics Committee.
Trial registration number
NCT05162924 .
... 68 In a small study by Selano and Grostic, it was found that upper cervical adjustments increased CD4 helper T-cell counts by 48 percent over the six-month duration of the study. 69 Teodorczyk-Injeyan showed that chiropractic treated subjects have also shown attenuation of lipopolysaccharide induced production of the inflammatory cytokines unrelated to systemic levels of the neurotransmitter substance P. 70 Research has explored the relationship of spinal manipulation, spino-autonomic reflexes and their influence on activity of immune and inflammatory cells. This research has shown a reduction in pro-inflammatory cytokines after spinal manipulation. ...
Objective: To discuss the existing literature on chiropractic, vertebral subluxation and immune function in order to inform the development of an integrative review of the literature, a review of immune biomarkers in relation to chiropractic, development of a research protocol, the implementation of future studies and the development of related policy.
Methods/Results: We conducted a scoping review of existing literature available to the authors and conducted further searches and gathering of documents based on that available literature. 125 papers were gathered and included in this review.
Conclusions: This is a scoping review of the literature regarding chiropractic and its relationship to neuroimmunology. It is intended to inform a larger project and give that team as much background as possible in a short period of time. The results of the already available research demands that we further explore the neuro-immuno-regulatory effects of chiropractic, adjustment and spinal manipulation and it provides a starting point for doing so. While adjustments reduce pain and inflammation, they also improve immune-regulatory function. How and to what extent is the subject of this current multi-pronged project.
Key Words: Chiropractic, immunity, neuroimmunity, neuroimmunology, psychoneuroimmunology, neuroimmunoendocrine system, immune biomarkers, supersystem, vertebral subluxation, adjustment, spinal manipulation
... 68 In a small study by Selano and Grostic, it was found that upper cervical adjustments increased CD4 helper T-cell counts by 48 percent over the six-month duration of the study. 69 Teodorczyk-Injeyan showed that chiropractic treated subjects have also shown attenuation of lipopolysaccharide induced production of the inflammatory cytokines unrelated to systemic levels of the neurotransmitter substance P. 70 Research has explored the relationship of spinal manipulation, spino-autonomic reflexes and their influence on activity of immune and inflammatory cells. This research has shown a reduction in pro-inflammatory cytokines after spinal manipulation. ...
A growing body of evidence supports our understanding of the role of the nervous system in immune system function. Basic science studies and clinical reports in the scientific literature provide supportive evidence of the beneficial effects of chiropractic care in improving function, including immune system function and quality of life. These guidelines support chiropractic practice in an evidence-informed, patient centered model. Evidence-informed practice involves the integration of the knowledge and experience of the chiropractor, the best available research evidence, and the needs and preferences of individual patients. Furthermore, chiropractors must be free to discuss, publish, and otherwise disseminate the best available evidence, and in practice, apply it to the needs of individual patients.
The aim is to present for osteopaths the modern ideas about somatic dysfunctions as potentially reversible structural and functional disorders in the human body, and about its diagnostics and the correction possibilities.
A specifi c subject of osteopathic infl uence is a group of palpable phenomena, which are called somatic dysfunctions. Somatic dysfunctions are included in the International Classifi cation of Diseases, Injuries and Conditions Affecting Health, 10th Revision (ICD-10). Somatic dysfunction (SD) is a potentially reversible structural and functional disorder in tissues and organs, manifested by palpation-determined limitations of various types of movements and mobility. Reversibility is one of the main characteristics of SD, associated with the ability to obtain the effect of changing/eliminating the identifi ed disorders in response to various methods of osteopathic correction. Impaired mobility, that is, SD, can have several components that can be combined with each other and have different degrees of severity — biomechanical, hydrodynamic (rhythmogenic) and neurodynamic. SD can manifest itself at the global, regional and local levels, and can have an acute or chronic character. The leading role in the pathogenesis of SD formation belongs to the connective tissue. Based on anamnestic data, physical examination, as well as using the algorithm of palpation diagnostic techniques, osteopaths determine the relative position of the body structures and their symmetry, as well as the qualitative state of the tissues. In addition to the generally accepted formulation of the diagnosis, an osteopathic conclusion includes the indication of biomechanical, rhythmogenic and neurodynamic disorders at the global, regional and local levels, as well as the dominant SD, the correction of which will be the logical ultimate goal of the osteopathic session. In accordance with the current regulatory framework, the osteopathic physician at the appointment fi lls out the form «Primary examination by an osteopathic physician» or the form «Examination by an osteopathic physician (observation in dynamics)». These medical documents are an insert in the Registration Form № 025/u, approved by the order of the Ministry of Health of Russia dated December 15, 2014 № 834n. The restoration of mobility is the goal of osteopathic treatment techniques applying and leads to the normalization of the functional state of tissues. The practice of osteopathy is to release the elements of the musculoskeletal system, internal organs, to restore the proper functioning of all body systems, including the nervous, circulatory and lymphatic systems. In the absence of contraindications (absolute or relative), the treatment regimen is determined individually in accordance with the issued osteopathic conclusion, including the defi ning of the number, nature (type) of techniques and the sequence of their use in a given session. The effectiveness of osteopathic correction of SD has been proven for various diseases and conditions, a list of which is also presented in the Recommendations.
Conclusion . The implementation of the Clinical Recommendations can contribute to the timely diagnosis and improve the quality of medical care for patients with SD.
Introduction. Tension-type headache (TTH) is known to be the most common type of headache in all age groups. The guidelines of the European Federation of Neurological Societies, the Italian Guidelines for Primary Headaches and the Italian Consensus Conference on Pain in Neurorehabilitation report that non-pharmacological therapies are valid adjunctive treatments for TTH. Previous studies have shown that the use of general osteopathic treatment in patients with TTH is accompanied by a significant decrease in the severity of pain syndrome and asthenic condition. We did not find any scientific publications devoted to the objectification of the results of osteopathic correction in TTH using magnetic resonance imaging (MRI).
The aim of the study was to objectify the results of osteopathic correction by assessing changes in the liquor dynamics of the posterior cranial fossa in patients with tension-type headache.
Materials and methods . The study was conducted from December 2020 to December 2021 at the clinic of the Center for New Medical Technologies, Novosibirsk. There were under the observation 10 patients with an established diagnosis of TTH aged from 18 to 55 years, 4 men, and 6 women. All patients before the start of treatment and after the course completion were assessed for their osteopathic status and underwent high-field MRI 3T of the brain with the calculation of the posterior cranial fossa restriction index (CFRI). CFRI reflects the state of liquorodynamics at the level of the skull base and shows the level of freedom in the relationship between fluid spaces and brain tissues. Study participants received a course of osteopathic correction, which included 3–4 procedures with an interval of 5–7 days. The observed patients did not receive any other therapy during the study period.
Results. The examined patients were most characterized by regional biomechanical disorders (RBD): head (9); neck, structural component (5); thoracic, visceral component (5); dura mater region (9). In terms of severity, mild RBD prevailed (1 point). After treatment, patients have a decrease of the detection frequency of major regional somatic dysfunctions (SD). Statistically significant differences (p<0,05) were obtained in the SD incidence of head region; neck region, structural component; thoracic, visceral component; dura mater region. A statistically significant (p<0,05) increase in the mean CFRI from 30,22±0,63 to 31,78±0,73 % was found after the treatment.
Conclusion. The results of the high-field MRI with the study of CFRI allow to quantitatively assess the changes of the cerebrospinal fluid dynamics in patients with tension-type headache, and it can be used as an objective criterion for the osteopathic correction results and the therapy clinical effectiveness. The study should be continued with a more representative sample.
Purpose: the aim of this study was to determine the principal differences of changes in the cardiorespiratory system activity under the influence of traction manipulations in the thoracic spine of men and women.
Material & Methods: the 26 adults were involved in the study, including 18 women aged 39.6±12.1 years and 8 men aged 36.3±8.3 years. All patients were diagnosed with osteochondrosis of the thoracic spine, which was confirmed by radiographic examination. The study of the cardiorespiratory system was conducted in the first procedure of SMT before and after the use of traction manipulations directly in the physician office. The integrated method of studying the cardiorespiratory system defined as spiroarteriocardiorhythmography (SACR) was used. It simultaneously records the heart rate, rhythms of systolic and diastolic pressure at each heartbeat and respiratory rhythms, which provides significant time savings to determine the functional state of the heart, vessels and respiration, as well as to identify the important parameters of their interaction.
Results: characterizing the changes in the cardiorespiratory system as a whole under the influence of traction manipulations on the thoracic spine, it should be noted that men and women had some significant unidirectional changes in HR (min–1), CO (dm3), CI (dm3/m2), IH (n. u.), which are determined primarily by the decrease in HR (min–1) under the influence of traction manipulations. As to the men, the significant effects were more related to the impact on the contractile function of the heart, which was confirmed by the improvement of the electrical systole of the ventricles (QTC, s), the increase in the activity of the effects of the parasympathetic branch of the ANS on the cardiac rhythm (HF, ms2) and a certain increase in the stroke index within the normative values (SI, cm3/m2), then to the women the significant effects were more related to the influence on the breathing pattern and vascular tone. Thus, characteristic and positive effects in women can be considered a decrease in the variability of diastolic blood pressure in the very-low-frequency range (VLFDBP, mmHg2), which is combined with a decrease in the total power of diastolic pressure variability (TPDBP, mmHg2) and an increase in the total peripheral vascular resistance (GPVR, dyn/s/cm−5).
Conclusions: summarizing the results of the impact of traction manipulations in the thoracic spine on the cardiorespiratory system of men and women, it can be stated that their effect is different and has features associated with the use of different mechanisms. For men, the predominant effect is on the heart contractile function, and for women it is on the respiratory system and autonomous regulation of vascular tone.
Animal physical rehabilitation is one of the fast-growing fields in veterinary medicine in recent years. It has become increasingly common in small animal practice and will continue to emerge as an essential aspect of veterinary medicine that plays a vital role in the care of animals with physical impairments or disabilities from surgery, injuries, or diseases.1 This is true now more than ever because of the increasing advances in lifesaving treatments, the increased lifespan of companion animals, and the growth of chronic conditions, of which many are associated with movement disorders. The American Association of Rehabilitation Veterinarians (AARV) defines APR as "the diagnosis and management of patients with painful or functionally limiting conditions, particularly those with injury or illness related to the neurologic and musculoskeletal systems." Rehabilitation not only focuses on recovery after surgical procedures but also on improving the function and quality of life in animals suffering from debilitating diseases such as arthritis or neurologic disorders. The overall goal of APR is to decrease pain, reduce edema, promote tissue healing, restore gait and mobility to its prior activity level, regain strength, prevent further injury, and promote optimal quality of life. Typically, a multimodal approach with pharmaceutical and nonpharmaceutical interventions is used by APR therapists to manage patients during their recovery. The purpose of this article aims to provide knowledge and guidance on physical rehabilitation to help veterinarians in the proper return of their patients with ZCA safely after injury and/or surgery.
This review outlines the mechanisms underlying the interaction between the nervous and immune systems of the host in response to an immune challenge. The main focus is the cholinergic anti-inflammatory pathway, which we recently described as a novel function of the efferent vagus nerve. This pathway plays a critical role in controlling the inflammatory response through interaction with peripheral a7 subunit-containing nicotinic acetylcholine receptors expressed on macrophages. We describe the modulation of systemic and local inflammation by the cholinergic anti-inflammatory pathway and its function as an interface between the brain and the immune system. The clinical implications of this novel mechanism also are discussed.
It is widely presumed that in addition to CD14, other molecules are necessary for lipopolysaccharide (LPS)-induced cell activation. In order to shed light on some of the biological and biochemical properties of these molecules, we examined the LPS responsiveness of CD14-negative, ST2 cells. Although ST2 cells do not express CD14 mRNA, they, nonetheless, expressed IL-6 mRNA and synthesized IL-6 protein when incubated with LPS in serum-free medium (i.e. without soluble CD14). Paxlitacel (Taxol™) also induced IL-6 mRNA expression in ST2 cells, while Rhodobacter sphaeroides diphoshoryl lipid A (RsDPLA) inhibited both LPS- and Taxol-induced expression of IL-6 mRNA. Collectively, these data suggest that LPS, RsDPLA, and Taxol all recognize the same receptor complex on ST2 cells and do not require the participation of CD14. In addition, using antibody raised against the ST2 cell membrane fraction, we detected a set of LPS-specific membrane antigens in murine peritoneal macrophages, including two designated p57 (57 kDa) and p53 (53 kDa). There was no qualitative difference in the expression of p57 and p53 in LPS-responsive, C3H/HeN and LPS-hyporesponsive, C3H/HeJ macrophages. However, after stimulating the macrophages with LPS or Taxol, expression of p57 and p53 was diminished in C3H/HeN macrophages, but not in C3H/HeJ macrophages. Phorbol ester (PMA) and A23187 calcium ionophore did not suppress p57 or p53 expression, and the lipid A precursor, PE406, did not bind to either protein. Thus, p57 and p53 may play important roles in LPS-evoked responses, but they do not appear to serve as LPS receptors.
Monocytes from different individuals show variable cytokine production in response to a variety of stimuli. We wished to determine the sets of conditions (cytokine combinations) that would enable us to demonstrate stable inter-individual differences in the production of IL-1α, IL-1β, IL-1Ra, IL-6 and tumour necrosis factor-alpha (TNF-α) by monocytes. We assessed the ability of a number of recombinant human cytokines (granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-γ), TNF-α, IL-4, IL-6, transforming growth factor-beta (TGF-β), IL-10 and IL-1Ra) to stimulate or inhibit the production of one or more of these monocyte products. GM-CSF was found to stimulate the production of all five of these cytokines in a highly reproducible manner. TNF-α also up-regulated production of IL-1α, IL-1β, IL-1Ra and IL-6 by monocytes, but the variability in the results of cells cultured from the same individuals on different occasions was greater. Other cytokines either stimulated production of only some of the five cytokine products tested, or stimulated the production of some cytokine products while inhibiting production of others. This was especially evident when cytokines were used in combination with GM-CSF: IFN-γ down-regulated production of IL-1Ra while up-regulating the production of IL-1α/β, IL-6 and TNF-α, while IL-4 had the exact opposite effect. Polymorphisms in regions of cytokine genes that affect transcription may account for some of the inter-individual variation in cytokine production. We have shown that a stable estimate of cytokine production phenotype can be obtained when monocytes collected on at least two separate occasions are stimulated by GM-CSF in vitro. We have looked for a relationship between IL-1 production and an 86-bp variable repeat polymorphism in intron 2 of the IL-1Ra gene. A less common allele of this polymorphism (allele 2) was associated with increased production of IL-1Ra protein, and also reduced production of IL-1α protein by monocytes.
The effect of spinal manipulation on the respiratory burst of polymorphonuclear neutrophils (PMN) and monocytes from treated adults was measured by zymosan-stimulated chemiluminescence (CL). Peripheral blood was collected 15 min before and 15 min after treatment (sham manipulation, thoracic spine manipulation, or soft tissue manipulation), the cells were isolated, challenged with a standardized, opsonized luminol-containing suspension of zymosan, and monitored for CL. Plasma from two subsets of subjects was radioimmunoassayed for Substance P (SP). PMN were also preincubated with SP in vitro over the dose range 5 x 10(-12) M to 5 x 10(-8) M and the CL response monitored. The CL responses of both PMN and monocytes from subjects who received spinal manipulation were significantly higher after than before treatment, and significantly higher than the response in sham or soft-tissue treated subjects. Measurement of the force applied by sham and spinal manipulation suggested a force threshold for the enhancement of the CL response. Plasma levels of SP before and after treatment in sham treated subjects did not differ significantly; however, elevated plasma SP was observed in subjects after spinal manipulation. Preincubation of PMN with 1 x 10(-11) M, 5 x 10(-11) M or 1 x 10(-10) M SP in vitro primed PMN for an enhanced respiratory burst when the cells were subsequently challenged
A critical need in assessing the clinical utility of manipulative therapy for back pain is the identification of biological changes associated with the forces applied by spinal manipulation. Such changes could then serve as markers for both sham treatment and manipulation. We determined the priming of polymorphonuclear neutrophils for an enhanced respiratory burst and its duration, the priming of mononuclear cells for enhanced endotoxin-stimulated tumor necrosis factor production and plasma levels of substance P following a single thoracic spine manipulation. There was a significant difference in the respiratory burst of polymorphonuclear neutrophils in response to a particulate challenge, depending on the time of blood sample collection. The response of polymorphonuclear neutrophils isolated from blood collected 15 min after manipulation was significantly higher than the response of cells isolated from blood collected 15 min before and 30 and 45 min after manipulation. Mononuclear cells were also primed for enhanced endotoxin-stimulated tumor necrosis factor production by spinal manipulation. Both of these priming effects were accompanied by a slight, but significant elevation in plasma substance P. The mean manipulation force associated with these biological effects was 878 +/- 99 N. These biological effects may provide a means of monitoring the delivery of both sham and manipulative treatment and, therefore, provide a crucial tool for understanding the efficacy of manipulative therapy