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Parastouei K, Solaymani-Mohammadi F, Shiri-Shahsavar MR, Chahardoli R, Nasl-Khameneh AM, Zarandi MB, Ghotloo S, Saboor-Yaraghi AA. The effect of calcitriol and all-trans retinoic acid on T-bet, IFN-γ, GATA3 and IL-4 genes expression in experimental autoimmune encephalomyelitis. APMIS 2020; 128:583-592. [PMID: 32865844 DOI: 10.1111/apm.13073] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 08/12/2020] [Indexed: 01/07/2023]
Abstract
Multiple sclerosis (MS) is an immune-mediated inflammatory disease which affects the central nervous system (CNS). In the present study, the in vivo effects of ATRA, calcitriol, and their combinations on the expression of murine CD4+ T cell cytokines and their specific transcription factors in experimental autoimmune encephalomyelitis (EAE)-induced mice were explored. Thirty-two EAE induced inbred C57BL/6 female mice with an age ranged from 8 to 10 weeks were divided into four categories in a random manner. The first, second, and third groups received ATRA, calcitriol, ATRA+ calcitriol, respectively, and the fourth group received vehicle. The treatment started on the day prior to immunization and through the IP injections every other days for 21 days. The dosages of administration for calcitriol, ATRA, and calcitriol+ ATRA were 100 ng, 250 μg, and 50ng + 125 μg, respectively per mouse. An equal volume of excipient was administered for the vehicle group. T-bet, IFN-γ, GATA-3, and IL-4 genes expression were assessed in the splenocytes of EAE -induced mice. The expression of T-bet and IFN-γ genes in the splenocytes of ATRA, calcitriol and combination- treated mice were significantly reduced compared to vehicle group (p < 0.05). A significant decrease in T-bet expression was observed in the combination-treated group compared to the ATRA-treated group (p < 0.05). The expression of GATA3 and IL-4 genes was significantly increased in the ATRA-, calcitriol-, and combination-treated mice when compared with the control group (p < 0.05). Furthermore, the effect of calcitriol alone and in combination with ATRA was more considerable than that of ATRA alone. The nutraceutical approaches may be promising in the prevention and/or treatment of MS.
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Affiliation(s)
- Karim Parastouei
- Department of Cellular and Molecular Nutrition, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | - Reza Chahardoli
- Department of Cellular and Molecular Nutrition, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mehdi Borhani Zarandi
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Somayeh Ghotloo
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Saboor-Yaraghi
- Department of Cellular and Molecular Nutrition, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Pizza V, Montella S, Luigi Iorio E, Silvestro A, Agresta A, Somma SD, Capasso A. Vitamin D Serum Level in Elderly Patients with Alzheimer’s Disease: Preliminary Analysis from Cilento Region. Open Neurol J 2020. [DOI: 10.2174/1874205x02014010063] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Introduction:
It is estimated that 46 million people in the world live with dementia and it is estimated that this number will increase 3-fold by 2050, being a leading cause of disability worldwide and major welfare and economic problem. The aging of the general population increase these problems, especially in regions, such as Cilento (Southern Italy), where we can register higher longevity. Preserving cognitive health is one of the most important aims of the current research, also through the identification of possible preventative life-style strategies. Recent meta-analyses suggest that low serum vitamin D concentrations could be associated with Alzheimer's disease (AD) and cognitive impairment. The specific role of Vitamin D, however, is still controversial. There is a growing evidence of high rates of vitamin D deficiency in the elderly and there is still much uncertainty about the cause of AD and other forms of dementia. On the other hand, there is no definitive evidence is not conclusive and vitamin D could be involved in many other physiological and pathological mechanisms.
Objective:
Our aim is to investigate vitamin D serum levels in a small preliminary sample of AD patients from the Cilento area.
Materials and Methods:
Patients were recruited from the AD centre of the San Luca Hospital, in Vallo della Lucania (SA). We enrolled 25 consecutive patients, 13 women, and 12 men. The mean age was 78.5±8.3 years, the mean duration of the disease was 3.5±1.8 years. The average school-age of the patients was 6.1 +/- 3.5 years, the average disease age was 6.3 +/- 1.7 years, the average basal Mini-Mental Score Examination (MMSE) score was 17.6 +/- 3.6. We determined serum 25-hydroxyvitamin D (25[OH]D) in 25 consecutive AD patients.
Results:
The mean vitamin D serum level was 17.9+7.9 UI/ml, denoting a state of insufficiency. Among our 25 patients, only 3 had serum level above 30 UI/ml; most patients (17 out of 25) showed serum level among 10 and 30 UI, while in 5 patients, serum level was less than 10 UI.
Conclusion:
Our preliminary data showed that Vitamin D deficiency was, in our patients, independently associated with AD, even in a special population, high rate of centenarians, like Cilento people. However, our preliminary study has different limitations. The vitamin D deficiency has been evaluated through a single time-point of measurement (or in different periods of the year), that may be susceptible to bias. Even the differences in age and level of education should be taken into consideration. Nevertheless, these data in the Cilento region are original (there are no similar reports to our knowledge). However, our results confirm the necessity of other study, and this result is an important opportunity to introduce a modifiable risk fact and, consequently, a new treatment for AD.
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Kan E, Kan EK, Yücel ÖE. The Possible Link Between Vitamin D Levels and Exudative Age-related Macular Degeneration. Oman Med J 2020; 35:e83. [PMID: 31993223 PMCID: PMC6975258 DOI: 10.5001/omj.2020.01] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 03/18/2019] [Indexed: 01/24/2023] Open
Abstract
Objectives We sought to evaluate the possible correlation between serum vitamin D levels and exudative age-related macular degeneration (AMD). Methods We conducted a cross-sectional study including 95 patients with exudative AMD and 95 healthy age- and sex-matched controls. The participants’ serum 25-hydroxyvitamin D3 (25(OH)D3) levels were measured, and the results were classified into three categories: deficient (< 20.0 ng/mL), insufficient (20.1–29.9 ng/mL), and sufficient (>30.0 ng/mL). We compared serum 25(OH)D3 levels between the two study groups and the AMD ratio between the patients with deficient serum 25(OH)D3 levels and those with levels in the sufficient and insufficient ranges. Results The median 25(OH)D3 levels were significantly lower in patients with AMD compared to the control subjects (p = 0.042). The frequencies of patients with AMD among the vitamin D categories were statistically significant (p = 0.043). Subgroup analysis showed that the frequency of patients with AMD and deficient vitamin D levels was significantly higher than that found in the patients who had sufficient and/or insufficient ranges of vitamin D levels (55.0% vs. 36.0%, p = 0.043, respectively). Conclusions Serum 25(OH)D3 levels may have an impact on the neovascular type of AMD. As 25(OH)D3 levels decrease, the frequency of AMD increases.
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Affiliation(s)
- Emrah Kan
- Department of Ophthalmology, Samsun Training and Research Hospital, Samsun, Turkey
| | - Elif Kılıç Kan
- Department of Endocrinology and Metabolism, School of Medicine, Ondokuz Mayıs University, Samsun, Turkey
| | - Özlem Ekşi Yücel
- Department of Ophthalmology, School of Medicine, Ondokuz Mayıs University, Samsun, Turkey
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Hashemi R, Bandarian M, Abedi-Taleb E, Khojasteh H, Khedmat L, Asadollahi E, Beytollahi M, Jelodar AM. The association between blood vitamins D and E with age-related macular degeneration: A pilot study. Interv Med Appl Sci 2019; 10:127-132. [PMID: 30713750 PMCID: PMC6343581 DOI: 10.1556/1646.10.2018.22] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Background This study was aimed to evaluate the association of serum vitamins D and E level with age-related macular degeneration (AMD). Methods This pilot study was performed in two groups of 15 patients in treatment group and 15 patients in control group. Measurements of blood factors [such as C-reactive protein (CRP) and high-density lipoprotein (HDL)] were performed after 12 h of fasting. To measure vitamins D and E, the serum was isolated from 5 cc blood samples. Results HDL was higher in the control group as compared with the AMD group. However, no significant difference was found between the two groups (p = 0.08). On the other hand, serum vitamin E in the AMD group was remarkably higher as compared to the control group (p < 0.002). However, no significant difference was found in serum vitamin D levels between the two groups (p = 0.662). Our findings also revealed that there was no statistically significant relationship between BMI and AMD. Moreover, no significant correlation was determined between serum CRP and AMD (p = 0.96). Conclusions Our data indicated that none provides evidence for associations between AMD and serum vitamin D levels. The association between vitamin D and AMD requires further investigations in a large population studies, to elucidate whether vitamin D deficiency can be an important risk factor for AMD.
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Affiliation(s)
- Rezvan Hashemi
- Department of Geriatric Medicine, Ziaeian Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahin Bandarian
- Department of Obstetric and Gynecology, Ziaeian Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Elahe Abedi-Taleb
- Ziaean Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hassan Khojasteh
- Ophthalmology Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Khedmat
- Department of Community Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Faculty of Medicine, Department of Community Medicine, Health Management Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Elnaz Asadollahi
- Ziaean Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Beytollahi
- Department and Faculty of Medical Sciences and Technology, Islamic Azad University, Tehran, Iran
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Goswami R, Kaplan MH. Essential vitamins for an effective T cell response. World J Immunol 2016; 6:39-59. [DOI: 10.5411/wji.v6.i1.39] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 10/07/2015] [Accepted: 11/25/2015] [Indexed: 02/06/2023] Open
Abstract
Effective adaptive immune responses rely upon appropriate activation of T cells by antigenic peptide-major histocompatibility complex on the surface of antigen presenting cells (APCs). Activation relies on additional signals including co-stimulatory molecules on the surface of the APCs that promote T cell expansion. The immune response is further sculpted by the cytokine environment. However, T cells also respond to other environmental signals including hormones, neurotransmitters, and vitamins. In this review, we summarize the mechanisms through which vitamins A and D impact immune responses, particularly in the context of T cell responses.
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Hayes CE, Hubler SL, Moore JR, Barta LE, Praska CE, Nashold FE. Vitamin D Actions on CD4(+) T Cells in Autoimmune Disease. Front Immunol 2015; 6:100. [PMID: 25852682 PMCID: PMC4364365 DOI: 10.3389/fimmu.2015.00100] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 02/23/2015] [Indexed: 12/11/2022] Open
Abstract
This review summarizes and integrates research on vitamin D and CD4+ T-lymphocyte biology to develop new mechanistic insights into the molecular etiology of autoimmune disease. A deep understanding of molecular mechanisms relevant to gene–environment interactions is needed to deliver etiology-based autoimmune disease prevention and treatment strategies. Evidence linking sunlight, vitamin D, and the risk of multiple sclerosis and type 1 diabetes is summarized to develop the thesis that vitamin D is the environmental factor that most strongly influences autoimmune disease development. Evidence for CD4+ T-cell involvement in autoimmune disease pathogenesis and for paracrine calcitriol signaling to CD4+ T lymphocytes is summarized to support the thesis that calcitriol is sunlight’s main protective signal transducer in autoimmune disease risk. Animal modeling and human mechanistic data are summarized to support the view that vitamin D probably influences thymic negative selection, effector Th1 and Th17 pathogenesis and responsiveness to extrinsic cell death signals, FoxP3+CD4+ T-regulatory cell and CD4+ T-regulatory cell type 1 (Tr1) cell functions, and a Th1–Tr1 switch. The proposed Th1–Tr1 switch appears to bridge two stable, self-reinforcing immune states, pro- and anti-inflammatory, each with a characteristic gene regulatory network. The bi-stable switch would enable T cells to integrate signals from pathogens, hormones, cell–cell interactions, and soluble mediators and respond in a biologically appropriate manner. Finally, unanswered questions and potentially informative future research directions are highlighted to speed delivery of etiology-based strategies to reduce autoimmune disease.
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Affiliation(s)
- Colleen Elizabeth Hayes
- Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison , Madison, WI , USA
| | - Shane L Hubler
- Department of Statistics, College of Letters and Sciences, University of Wisconsin-Madison , Madison, WI , USA
| | - Jerott R Moore
- Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison , Madison, WI , USA
| | - Lauren E Barta
- Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison , Madison, WI , USA
| | - Corinne E Praska
- Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison , Madison, WI , USA
| | - Faye E Nashold
- Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison , Madison, WI , USA
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Gorter EA, Hamdy NAT, Appelman-Dijkstra NM, Schipper IB. The role of vitamin D in human fracture healing: a systematic review of the literature. Bone 2014; 64:288-97. [PMID: 24792958 DOI: 10.1016/j.bone.2014.04.026] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 04/10/2014] [Accepted: 04/23/2014] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Vitamin D is essential for bone mineralization and for the subsequent maintenance of bone quality. Mineralization is part of hard callus formation and bone remodelling, processes, which are part of fracture healing. We provide a comprehensive review of the literature to summarize and clarify if possible, the cellular effects of vitamin D and its clinical involvement in the process of fracture healing in human. MATERIAL AND METHODS We conducted a literature search in PubMed, Embase (OVID version), and Web of Science. RESULTS A total of 75 in vitro and 30 in vivo studies were found with inconsistent results about the cellular effect of vitamin D on fracture involved inflammatory cells, cytokines, growth factors, osteoblasts, osteoclasts and on the process of mineralization. With only five in vitro studies performed on material derived from a fracture site and one in vivo study in fracture patients, the exact cellular role remains unclear. Seven studies investigated the circulating vitamin D metabolites in fracture healing. Although it appears that 25(OH)D and 24,25(OH)2D3 are not affected by the occurrence of a fracture, this might not be the case with serum concentrations of 1,25(OH)2D3. The potential clinical effect of vitamin D deficiency is only described in one case series and three case controlled studies, where the results tend to show no effect of a vitamin D deficiency. No clinical studies were found investigating solely vitamin D supplementation. Two clinical studies found a positive effect of vitamin D supplementation and calcium, of increased bone mineral density or respectively increased fracture callus area at the fracture site. One study found indirect evidence that vitamin D and calcium promoted fracture healing. CONCLUSION Despite these results, and the presumed beneficial effect of vitamin D supplementation in deficient patients, clinical studies that address the effects of vitamin D deficiency or supplementation on fracture healing are scarce and remain inconclusive. We conclude that vitamin D has a role in fracture healing, but the available data are too inconsistent to elucidate how and in what manner.
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Affiliation(s)
- Erwin A Gorter
- Department of Surgery and Traumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
| | - Neveen A T Hamdy
- Department of Endocrinology and Metabolic Diseases, and Centre for Bone Quality, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
| | - Natasha M Appelman-Dijkstra
- Department of Endocrinology and Metabolic Diseases, and Centre for Bone Quality, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
| | - Inger B Schipper
- Department of Surgery and Traumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
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Abstract
OBJECTIVE Vitamin D insufficiency is highly prevalent, with particular subgroups at greater risk (e.g. the elderly and those with darker skin). Vitamin D insufficiency may partly explain US racial/ethnic disparities in the prevalence of periodontitis and tooth loss. We evaluated the association between a predictor score of plasma 25-hydroxyvitamin D (25(OH)D) and incidence of periodontitis and tooth loss. DESIGN Detailed biennial questionnaires were collected on medical history, lifestyle practices and incident periodontitis and tooth loss. The predictor score was derived from variables known to influence circulating concentrations of plasma 25(OH)D and validated against plasma concentrations among a sub-sample. Multivariable Cox proportional-hazards models with time-varying covariates estimated the association between the predicted 25(OH)D score and time until first tooth loss. SUBJECTS A total of 42,730 participants of the Health Professionals Follow-Up Study aged 40-75 years at baseline were followed from 1986 to 2006. SETTING USA, representing all fifty states and the District of Columbia. RESULTS We observed 13,581 incident tooth loss events from 539,335 person-years. There was a dose-dependent significant inverse association across quintiles of the predicted 25(OH)D score and incidence of tooth loss. In multivariable analyses, the highest quintile of the updated predicted 25(OH)D score compared with the lowest was associated with a 20% lower incidence of tooth loss (hazard ratio = 0.80, 95 % CI 0.76, 0.85; P value for trend <0.001); UV-B was also independently associated. Results for the predicted 25(OH)D score and periodontitis were similar. CONCLUSIONS These results are suggestive of an association between predictors of vitamin D and lower incidence of tooth loss and periodontitis.
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Reconsidering the connection between vitamin D levels and age-related macular degeneration. Eye (Lond) 2011; 25:1122-9. [PMID: 21818133 DOI: 10.1038/eye.2011.174] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
PURPOSE Recent evidence has suggested a correlation between reduced vitamin D levels and delayed angiogenesis and reduced inflammatory response, which are known to have a major role in the development and progression of age-related macular degeneration (AMD). DESIGN Cross-sectional study. PARTICIPANTS Members of the Maccabi Healthcare Services (MHS, one of the four largest Israeli Health Maintenance Organization) aged ≥60 years, whose vitamin D levels were taken as part of routine examinations between 2000 and 2008. METHODS All data for this study were obtained from MHS databases that include medical information on 1.8 million subscribers. MAIN OUTCOME MEASURES Serum 25-OH vitamin D levels. RESULTS The total study population comprised of 1045 members diagnosed as having AMD, and 8124 as non-AMD, for whom there was information on vitamin D levels. The mean±SD level of 25-OH vitamin D was 24.1±9.41 ng/ml (range 0.8-120) for the AMD patients and 24.13±9.50 ng/ml (range 0.0-120) for the controls (P=ns). One-third (33.6%) of the AMD patients and 32.86% of the controls had a 25-OH vitamin D level <16 ng/ml, and the proportions of tests in which the 25-OH vitamin D level was >74 ng/ml were 0.19 and 0.14%, respectively (P=ns). CONCLUSIONS No association was detected between vitamin D levels and the presence of AMD in this cross-sectional study. These results raise some doubt about an association between reduced vitamin D levels and the prevalence of AMD.
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Mauricio D, Mandrup-Poulsen T, Nerup J. Vitamin D Analogues in Insulin-Dependent Diabetes Mellitus and Other Autoimmune Diseases: A Therapeutic Perspective. ACTA ACUST UNITED AC 2009. [DOI: 10.1002/(sici)1099-0895(199603)12:1<57::aid-dmr157>3.0.co;2-l] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Puente J, Jaque M, Carrasco C, Cruz C, Valenzuela M, Wolf M, Mosnaim A. Triptan drugs, natural killer cell cytotoxicity, and neutrophils pro-matrix metalloproteinase-9 secretion. Headache 2008; 48:1482-9. [PMID: 18479418 DOI: 10.1111/j.1526-4610.2008.01136.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVE To study the effect of various triptan-like drugs, eg, avitriptan, naratriptan, and sumatriptan, as well as the benzopyran alnitidan, on the natural killer cell (NKC) activity of peripheral blood mononuclear cell (PBMC) samples and highly purified NKC (HPNKC) preparations. We also examined the possible role of these agents as immunomodulators by studying their effect upon the in vitro secretion of pro-matrix metalloproteinase-9 (pMMP-9) from whole blood and purified neutrophils samples. BACKGROUND The pharmacological profile of a large number of triptan-like compounds has been extensively studied. However, relatively little is known of their interactions with cellular components of the immune system. METHODS Blood was obtained from nonsmoking, drug-free healthy individuals from the Blood Bank of the University of Chile main Clinical Hospital (J.J.A.). PBMC were separated by centrifugation and HPNKC acquired by an immunomagnetic isolation procedure. NKC cytotoxicity was assayed using (51)Cr-labeled K-562 cells as target. Addition of drugs and of effector cells (30 : 1, 50 : 1, and 70 : 1 ratio for PBMCs, and 5 : 1 for HPNKCs) was followed by incubation. Paired Student's t-test (2-tailed) was used to determine the significance of the specific (51)Cr release in controls vs drug-treated samples. Aliquots of whole blood or purified neutrophils were added test drug, incubated, centrifuged, and the supernatant analyzed by gelatine zymography. Gelatinolytic activity was visualized, and a digested zone at MW 92 kD indicated presence of pMMP-9. Area of proteolysis was estimated by densitometry; prestained standards were used to assess pMMP-9 molecular weight. RESULTS Peripheral blood mononuclear cell's NKC cytotoxicity was consistently decreased after incubation with each and every one of the drugs tested. This result, observed for the 3 effector : target (E : T) cell ratios used, was relatively similar among the various compounds studied, and reached statistical significance only at E : T 70 : 1. Similar drug treatment failed, however, to produce significant changes in the cytotoxicity of HPNKC preparations, suggesting that modulation of the PBMC's NKC activity and that of HPNKC samples require different kinds of cell's derived signal. Incubation with either of the drugs tested failed to significantly alter (basal) nonstimulated pMPP-9 secretion by whole blood samples. However, basal pMMP-9 secretion by purified neutrophil preparations was significantly inhibited by alnitidan and sumatriptan, and not affected by naratriptan. CONCLUSIONS Various drugs with a triptan-like chemical structure interact with cellular components of the innate immune system, resulting in an apparent indirect inhibition of NKC activity and direct inhibition of neutrophils pMMP-9 secretion. These results suggest that they may play a positive role in decreasing the severity of inflammatory processes. Whether this effect is part of triptans antimigraine mechanism of action, or just an added beneficial effect of their use for the reversal treatment of migraine headaches remains to be explored.
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Affiliation(s)
- Javier Puente
- University of Chile - Biochemistry and Molecular Biology, Santiago, Chile
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Abstract
1,25-Dihydroxyvitamin D3(1,25(OH)2D3), the active form of vitamin D3, is a central player in Ca and bone metabolism. More recently, important immunomodulatory effects have been attributed to this hormone. By binding to its receptor, the vitamin D receptor, 1,25(OH)2D3regulates the expression of various genes and consequently affects the behaviour of different cell types within the immune system. 1,25(OH)2D3can potently inhibit pathogenic T cells and gives rise to elevated numbers of regulatory T cells via the induction of tolerogenic dendritic cells. These immunomodulatory activities of 1,25(OH)2D3have also been proven usefulin vivo: administration of 1,25(OH)2D3in several animal models can prevent or cure different autoimmune diseases and graft rejection. To overcome the dose-limiting side effects of 1,25(OH)2D3on Ca and bone, less calcaemic structural analogues (alone or in combination with synergistically acting drugs or bone-resorption inhibitors) have been successfully used in animal models. Furthermore, as 1,25(OH)2D3also contributes to host defence against infectious agents by the induction of antimicrobial responses, this molecule might provide a new strategy to deal with drug-resistant infections. According to the pleiotropic effects of 1,25(OH)2D3in the immune system, increasing epidemiological data underline the importance of adequate vitamin D intakes in reducing the risk of several autoimmune diseases and infections such as tuberculosis.
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Stio M, Treves C, Martinesi M, Bonanomi AG. Biochemical effects of KH 1060 and anti-TNF monoclonal antibody on human peripheral blood mononuclear cells. Int Immunopharmacol 2005; 5:649-59. [PMID: 15710334 DOI: 10.1016/j.intimp.2004.11.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2004] [Accepted: 11/03/2004] [Indexed: 12/13/2022]
Abstract
The aim of this study was to investigate whether the vitamin D analogue KH 1060 could exert a suppressive action on Tumor necrosis factor-alpha (TNF-alpha). The chimeric anti-TNF-alpha monoclonal antibody (anti-TNF), alone or in combination with KH 1060, was also used. KH 1060 (0.01, 0.1, 1 nM) significantly inhibited cell proliferation, determined after 5 days by [3H]thymidine incorporation, when peripheral blood mononuclear cells (PBMC), obtained from healthy subjects, were stimulated with phytohaemagglutinin (PHA) and incubated for 24 h in the absence and in the presence of lipopolysaccharide (LPS). In the same experimental conditions, anti-TNF exerted a significant inhibition on PBMC proliferation, at the lowest doses (0.001, 0.01 microg/ml) in the absence of LPS, and at 0.001, 1, 10 microg/ml in its presence. A synergistic inhibition was registered combining KH 1060 and anti-TNF, at well-defined concentrations. 0.1 nM KH 1060 produced a significant decrease in TNF-alpha levels, determined by ELISA, although less remarkable than in the presence of anti-TNF. This decrease was synergistic, associating 0.1 nM KH 1060 and 0.1 microg/ml anti-TNF. VDR protein levels were increased by 0.1 nM KH 1060, 0.1 microg/ml anti-TNF or their combination. The protein levels of two oncogenes, Bax and Bcl-2, remained unchanged, when PBMC were incubated with KH 1060, anti-TNF or their combination in the absence of LPS, while, in its presence, an increase was registered. The demonstrated anti-TNF-alpha effect of KH 1060 may suggest for this compound an immunosuppressive action and the possibility to synergistically act with other drugs.
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Affiliation(s)
- Maria Stio
- Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, I-50134 Florence, Italy.
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Njemini R, Abeele MV, Demanet C, Lambert M, Vandebosch S, Mets T. Age-related decrease in the inducibility of heat-shock protein 70 in human peripheral blood mononuclear cells. J Clin Immunol 2002; 22:195-205. [PMID: 12148594 DOI: 10.1023/a:1016036724386] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
We have investigated the effect of age and of the presence of proinflammatory cytokines on Hsp 70 production in human peripheral blood mononuclear cells, using flow cytometry. Twenty-seven women and 23 men, all apparently healthy, participated in the study. At 37 degrees C, the percentage of Hsp 70-producing monocytes and lymphocytes, as well as the level of Hsp 70 in monocytes, were negatively influenced by age. After exposure of the cells to 42 degrees C, the increase of Hsp 70 production was more pronounced in monocytes than in lymphocytes; both the intensity of Hsp 70 production and the percentage of Hsp 70-producing cells were negatively influenced by the age of the subjects, as well for monocytes as for lymphocytes. There was a negative correlation between the intensity of Hsp 70 production by monocytes exposed to 42 degrees C and the serum levels of tumor necrosis factor-alpha and interleukin-6. In conclusion, in human monocytes and lymphocytes, heat-induced Hsp 70 production is reduced with increasing age and is negatively influenced in monocytes by proinflammatory cytokines.
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Affiliation(s)
- R Njemini
- Geriatric Unit, Academic Hospital, Free University Brussels (VUB), Belgium
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Nonnecke BJ, Franklin ST, Reinhardt TA, Horst RL. In vitro modulation of proliferation and phenotype of resting and mitogen-stimulated bovine mononuclear leukocytes by 1,25-dihydroxyvitamin D3. Vet Immunol Immunopathol 1993; 38:75-89. [PMID: 7903011 DOI: 10.1016/0165-2427(93)90114-j] [Citation(s) in RCA: 28] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on the proliferation and phenotype of normal bovine peripheral blood mononuclear leukocytes (MNL) were studied in vitro. Resting and pokeweed mitogen (PWM)-stimulated MNL cultures were supplemented with 1.0 nM of 1,25(OH)2D3 at the beginning of the culture period. Leukocytes were removed from 2-, 4-, 6-, 8-, 10-, 12-, and 14-day unsupplemented and 1.25(OH)2D3-supplemented cultures, and were counted and phenotyped using monoclonal antibodies to bovine leukocyte surface antigens. Cell numbers in resting MNL cultures decreased with time and were unaffected by 1,25(OH)2D3 supplementation. The progressive increase in cell numbers in PWM-stimulated MNL cultures was suppressed, but not abolished by 1,25(OH)2D3. Suppression was greatest in PWM-stimulated 6- to 12-day cultures. Cellular composition of resting MNL cultures was unaffected by 1,25(OH)2D3. Pokeweed mitogen-stimulated cultures supplemented with 1,25(OH)2D3 had fewer total T-cells and CD4+ T-cells at 6-14 days. In contrast, numbers of CD8+ T-cells were significantly higher in 1,25(OH)2D3-supplemented cultures at 6, 10, and 14 days. Effects of 1,25(OH)2D3 on CD4+ and CD8+ T-cell populations were manifested by a significant reduction in the CD4+:CD8+ T-cell ratios in 6- to 14-day cultures. Proliferation of IL-2 receptor+ and MHC class II antigen+ cells was also reduced in supplemented 6- to 14-day cultures, indicating events associated with PWM-induced MNL activation were suppressed by 1,25(OH)2D3. These findings indicate that 1,25(OH)2D3 modulates the proliferation and differentiation of bovine MNL in vitro. Our results also suggest that changes in plasma or tissue 1,25(OH)2D3 concentrations that occur during the peripartum period and in clinical cases of milk fever may regulate the bovine immune system in vivo.
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Affiliation(s)
- B J Nonnecke
- United States Department of Agriculture, National Animal Disease Center, Ames, IA 50010-0070
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Abstract
This commentary has attempted to describe some of the new aspects of our knowledge of the immunological properties of 1 alpha,25(OH)2D3, the physiologically active metabolite of vitamin D3, and its new analogues. These analogues will, in the future, serve as tools to increase our understanding of the role of vitamin D in immunobiology, not only in basal research but also, hopefully, in the therapy of immune-mediated diseases.
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Affiliation(s)
- L Binderup
- Department of Biology, Leo Pharmaceutical Products, Ballerup, Denmark
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