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Receptor-mediated modulation of human monocyte, neutrophil, lymphocyte, and platelet function by phorbol diesters.

ABSTRACT: The tumor promoting phorbol diesters elicit a variety of responses from normal and leukemic blood cells in vitro by apparently interacting with cellular receptors. The biologically active ligand [20-(3)H] phorbol 12,13-dibutyrate ([(3)H]PDBu) bound specifically to intact human lymphocytes, monocytes, polymorphonuclear leukocytes (PMN), and platelets, but not to erythrocytes. Binding, which was comparable for all four blood cell types, occurred rapidly at 23 degrees and 37 degrees C, reaching a maximum by 20-30 min usually followed by a 30-40% decrease in cell associated radioactivity over the next 30-60 min. The time course for binding was temperature dependent with equilibrium binding occurring after 120-150 min at 4 degrees C, with no subsequent loss of cell-associated radioactivity at this temperature. Bound [(3)H]PDBu could be eluted by addition of unlabeled PDBu. Scatchard analysis of data from 4 degrees C binding studies revealed linear plots with high affinity receptors in these cell types with dissociation constants and receptors per cell of 60 nM and 7.8 x 10(5)/cell for lymphocytes, 51 nM and 15.5 x 10(5)/cell for monocytes, 38 nM and 4.0 x 10(5)/cell for PMN, and 19 nM and 2.9 x 10(4)/cell for platelets. Structure-activity studies using unlabeled phorbol-related compounds demonstrated a close correlation between their abilities to inhibit binding of [(3)H]PDBu to cells and their abilities to induce cellular responses (monocyte and PMN H(2)O(2) secretion, lymphocyte (3)HTdR incorporation, and platelet tritiated serotonin release); phorbol and 4-alpha phorbol were inactive while phorbol 12-myristate 13-acetate (PMA), PDBu, mezerein, and phorbol 12,13-diacetate (in decreasing order of potency) inhibited [(3)H]PDBu binding and elicited the various responses. Thus, these high affinity, specific receptors for the phorbol diesters, present on monocytes, lymphocytes, PMN, and platelets, mediate the pleiotypic effects induced by these ligands.

SUBMITTER: Goodwin BJ

PROVIDER: S-EPMC370277 | biostudies-other | 1982 Oct

REPOSITORIES: biostudies-other

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Receptor-mediated modulation of human monocyte, neutrophil, lymphocyte, and platelet function by phorbol diesters.

Goodwin B J BJ Weinberg J B JB

The Journal of clinical investigation 19821001 4

The tumor promoting phorbol diesters elicit a variety of responses from normal and leukemic blood cells in vitro by apparently interacting with cellular receptors. The biologically active ligand [20-(3)H] phorbol 12,13-dibutyrate ([(3)H]PDBu) bound specifically to intact human lymphocytes, monocytes, polymorphonuclear leukocytes (PMN), and platelets, but not to erythrocytes. Binding, which was comparable for all four blood cell types, occurred rapidly at 23 degrees and 37 degrees C, reaching a m ...[more]

PMID: 6956584

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Project description:BackgroundThe preoperative peripheral blood neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and monocyte-lymphocyte ratio (MLR) have been reported to be associated with the prognosis of various cancers but are always discussed separately. The aim of this study is to bring the combination of NLR, PLR and MLR into the prognostic assessment system of endometrial cancer (EC) and establish a nomogram to provide an objective prediction model for clinical decisions.MethodsA total of 1111 patients with EC who had accepted surgical treatment during 2013-2017 were involved in the analysis. Their NLR, PLR, and MLR levels were obtained from a routine blood examination within 2 weeks before operation. Receiver operating characteristic curve (ROC) analysis was performed to determine optimal cutoffs. Chi-square tests analysed the associations of the ratios with other clinicopathological variables. The prognostic value was indicated by overall survival (OS) via Cox proportional hazards models and Kaplan-Meier analysis. R software was used to establish the nomogram based on the combination of NLR, PLR, MLR and other clinicopathological factors.ResultsThe median follow-up period was 40 months, and the median age was 56. The enrolled patients were stratified by cutoffs of 2.14 for NLR, 131.82 for PLR and 0.22 for MLR. Multivariate analyses demonstrated that high NLR over 2.14 (HR = 2.71, 95%CI = 1.83-4.02, P<0.001), high PLR over 131.82 (HR = 2.75, 95%CI = 1.90-3.97, P<0.001), and high MLR over 0.22 (HR = 1.72, 95%CI = 1.20-2.45, P = 0.003) were significantly associated with worse OS. The combined indicator, high NLR + high PLR + high MLR (HR = 4.34, 95%CI = 2.54-7.42, P<0.001), showed the highest prognostic value. The Harrell's concordance index of the nomogram was 0.847 (95% CI = 0.804-0.890), showing good discrimination and calibration of this model.ConclusionThe combination of NLR, PLR, and MLR is a superior prognostic factor of EC. The nomogram involving the combination of NLR, PLR, MLR and other clinicopathological factors is recommended to predict OS for EC patients clinically.

Project description:BackgroundResearch on neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) in depression is still emerging and has increased 3-fold since the first meta-analysis. An updated meta-analysis with sufficient studies can provide more evidence for a potential relationship between NLR, PLR, MLR, and depression.MethodsWe identified 18 studies from the PubMed, EMBASE, Cochrane library, and Web of Science databases. Meta-analyses were performed to generate pooled standardized mean differences (SMDs) and 95% confidence intervals (CIs) between patients with depression and controls. Sensitivity analysis, subgroup analysis, meta-regression, and publication bias were conducted.ResultsA total of 18 studies including 2,264 depressed patients and 2,415 controls were included. Depressed patients had significantly higher NLR and PLR compared with controls (SMD = 0.33, 95% CI: 0.15-0.52, p < 0.001 and SMD = 0.24, 95% CI: 0.02-0.46, p < 0.05, respectively). MLR was slightly higher in depressed individuals compared to controls (SMD = 0.15, 95% CI: -0.26 to 0.55, p > 0.05), despite the absence of significance. Sensitivity analysis removing one study responsible for heterogeneity showed a higher and significant effect (SMD = 0.32, 95% CI: 0.20-0.44) of MLR. Three subgroup analyses of NLR, PLR, MLR, and depression revealed obvious differences in the inflammatory ratios between depressed patients and controls in China and the matched age and gender subgroup. Individuals with post-stroke depression (PSD) had higher NLR and MLR values as compared to non-PSD patients (SMD = 0.51, 95% CI: 0.36-0.67, p < 0.001 and SMD = 0.46, 95% CI: 0.12-0.79, p < 0.01, respectively). Meta-regression analyses showed that male proportion in the case group influenced the heterogeneity among studies that measured NLR values (p < 0.05).ConclusionsHigher inflammatory ratios, especially NLR, were significantly associated with an increased risk of depression. In the subgroup of China and matched age and gender, NLR, PLR, and MLR were all elevated in depressed patients vs. controls. Individuals with PSD had higher NLR and MLR values as compared to non-PSD patients. Gender differences may have an effect on NLR values in patients with depression.

Project description:BackgroundHemodialysis (HD) is the most important renal replacement therapy for patients with end-stage kidney disease (ESKD). Systemic inflammation is a risk factor of mortality in HD patients. Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) are new inflammatory markers. However, previous studies have inconsistent conclusions about the predictive value of NLR, MLR and PLR on mortality of HD patients. The aim of this study was to establish an inflammation scoring system by including NLR, MLR and PLR, and evaluate the association between the inflammation score and all-cause and cardiovascular mortality in HD patients.MethodsIn this single center retrospective cohort study, 213 incident HD patients from January 1, 2015 to December 31, 2020 were included. Baseline demographic and clinical data and laboratory measurements were collected. According to the optimal cut-off values, NLR, MLR and PLR were assigned 0 or 1 point, respectively. Then, the inflammation score was obtained by adding the NLR, MLR and PLR scores. All patients were followed until July 31, 2021. The associations of the inflammation score with all-cause and cardiovascular mortality were assessed by multivariable-adjusted Cox models.ResultsOf 213 patients, the mean (± SD) age was 56.8 ± 14.4 years, 66.2% were men, and 32.9% with diabetes. The primary cause of ESKD was mainly chronic glomerulonephritis (46.5%) and diabetic nephropathy (28.6%). The median inflammation score was 2 (interquartile range = 1-3). During a median 30 months (interquartile range = 17-50 months) follow-up period, 53 patients had died, of which 33 deaths were caused by cardiovascular disease. After adjusting for demographics, primary diseases and other confounders in multivariable model, the inflammation score = 3 was associated with a hazard ratio for all-cause mortality of 4.562 (95% confidence interval, 1.342-15.504, P = 0.015) and a hazard ratio for cardiovascular mortality of 4.027 (95% confidence interval, 0.882-18.384, P = 0.072).ConclusionIn conclusion, an inflammation scoring system was established by including NLR, MLR and PLR, and the higher inflammation score was independently associated with all-cause mortality in HD patients.

Project description:AimNeutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), or monocyte-lymphocyte ratio (MLR) has been shown to be related to the poor prognosis of cervical cancer, ovarian cancer, breast cancer, and other malignant tumors, but their role in predicting the prognosis of endometrial cancer is still controversial. Therefore, we conducted this meta-analysis to evaluate the effectiveness of NLR more accurately, PLR, or MLR in predicting the prognosis of endometrial cancer (EC).MethodsThis review systematically searched for relevant publications in databases of the Cochrane Library, PubMed, EMBASE, CNKI, WanFang, VIP, and CBM. Pooled hazard ratios (HR) with 95% confidence intervals (95% CI) were determined and used to explore the association between inflammatory biomarkers (NLR, PLR, and MLR) and overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) in a random-effects model. We also conducted subgroup analysis and publication bias in this meta-analysis. Stata 12.0 was used for statistical analysis.ResultsThis meta-analysis contained 14 eligible studies including 5,274 patients. Our results showed that NLR or PLR was associated with OS [NLR: HR, 2.51; 95% CI, 1.70-3.71; p <0.001 in univariate analysis (Ua); HR, 1.87; 95% CI, 1.34-2.60; p <0.001 in multivariate analysis (Ma); PLR: HR, 2.50; 95% CI, 1.82-3.43; p <0.001 in Ua; HR, 1.86; 95% CI, 1.22-2.83; p = 0.004 in Ma], but MLR was not associated with OS (HR, 1.44; 95% CI, 0.70-2.95; p = 0.325 in Ua; HR, 1.01; 95% CI, 0.39-2.60; p =0.987 in Ma). A further subgroup analysis found that the correlations were not affected by race, cutoff value, sample size, or treatment. Our meta-analysis showed that NLR or PLR was associated with DFS (NLR: HR, 2.50; 95% CI, 1.38-4.56; p =0.003 in Ua; HR, 2.06; 95% CI, 1.26-3.37, P =0.004 in Ma; PLR: HR, 1.91; 95% CI, 1.30-2.81; p = 0.001 in Ua), and NLR was associated with PFS only in the univariate analysis (HR, 1.71; 95% CI, 1.04-2.81; p =0.035 in Ua; HR, 1.79; 95% CI, 0.65-4.89; P =0.257 in Ma), but MLR was not associated with DFS (HR, 0.36; 95% CI, 0.03-4.13; p =0.409 in Ua).ConclusionsOur results indicated that pretreatment NLR and PLR were biomarkers of poor prognosis in patients with endometrial cancer. The results indicated that NLR or PLR was associated with OS and disease-free survival DFS, and NLR was associated with PFS only in univariate analysis, but MLR was not associated with OS or DFS.

Dataset Information

Receptor-mediated modulation of human monocyte, neutrophil, lymphocyte, and platelet function by phorbol diesters.

Publications

Receptor-mediated modulation of human monocyte, neutrophil, lymphocyte, and platelet function by phorbol diesters.

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