Intracellular IL-10 detection in T cells by flowcytometry: The use of protein transport inhibitors revisited
Anne-Hilde Muris, Jan Damoiseaux, Joost Smolders, Jan Willem Cohen Tervaert, Raymond Hupperts, Mariëlle Thewissen. Journal of Immunological Methods 2012.
In the past two decades, interleukin-10 (IL-10) has gained much attention as an important regulatory cytokine involved... more
In the past two decades, interleukin-10 (IL-10) has gained much attention as an important regulatory cytokine involved in self-tolerance. Functional assessment of IL-10 producing immune cells is traditionally done by stimulation and measurement of cytokine production by flowcytometry. Thereby a protein transport inhibitor like monensin is used to accumulate the cytokine of interest intracellularly. In this study we elaborated on the monensin effect on cytokine detection and focused on IL-10 detection in human T cells.
Peripheral blood mononuclear cells (PBMC) of 32 study subjects were isolated and stimulated with PMA/ionomycin, in the absence and presence of monensin, and stained intracellularly for IFN-γ, IL-4, IL-10 and IL-17A.
Our results re-established that detection of IFN-γ+ and IL-4+ T cells benefited from the presence of monensin during stimulation. However, stimulation in the presence of monensin yielded lower proportions of IL-10+ T cells (0.45% (0.28–0.80) versus 0.80% (0.50–1.50) of CD4+ T cells, p < 0.01), although monensin addition did result in an increased MFI (2431 (1273–4959) versus 1928 (1147–3760), p < 0.01). Detectable fractions of IL-17A+ CD4+ T cells were not affected by monensin. A shorter incubation time, but not lower monensin concentrations, was effective in improving the detection of IL-10+ T cells. We found a strong correlation between the fraction of IL-10+ CD4+ T cells in the presence and absence of monensin (R = 0.80 p < 0.01). Next to this, also the detection of IL-10+ NK-T cells and IL-10+ monocytes, but not IL-10+ B cells, is impaired in the presence of monensin.
This study shows that the effect of monensin on cytokine accumulation is time and cytokine dependent. Due to the use of monensin, previous research may have underestimated the number of IL-10+ leukocytes or may even have not been able to detect them at all. It is important to consider this for future research or when interpreting historical IL-10 data.
Indoleamine 2,3-Dioxygenase Activation and Depressive Symptoms In Patients With Coronary Artery Disease
Walter Swardfager, Nathan Herrmann, Yekta Dowlati, Paul I Oh, Alexander Kiss, Scott E Walker, Krista L Lanctôt. Psychoneuroendocrinology. 2009 Nov;34(10):1560-6.
An increase in immune-stimulated synthesis of kynurenine from tryptophan by indoleamine 2,3-dioxygenase (IDO) has been... more An increase in immune-stimulated synthesis of kynurenine from tryptophan by indoleamine 2,3-dioxygenase (IDO) has been observed in patients with coronary artery disease (CAD). However, neuropsychiatric correlates of IDO activation remain unexplored. We hypothesize that IDO activation, as measured by the kynurenine to tryptophan (K/T) ratio, is associated with depressive symptoms in those with CAD. This cross-sectional study recruited subjects with CAD (n=95) from a cardiac rehabilitation facility. Demographic, anthropometric and cardiac data were obtained by chart review. Patients using an antidepressant were excluded. The presence of a major depressive episode or minor depression was assessed using a structured clinical interview for depression based on Diagnostic and Statistical Manual 4th edition criteria. The Center for Epidemiological Studies-Depression Scale (CES-D) was used to quantify depressive symptoms. A standardized exercise stress test was used to assess cardiopulmonary fitness as summarized using the peak volume of oxygen consumption (Peak VO(2)). Kynurenine and tryptophan were assayed from fasting plasma samples to obtain the K/T ratio. Higher K/T ratios were significantly associated with higher CES-D scores (beta=.322, p=.002) in a linear regression controlling for time since most recent acute coronary syndrome (tACS), age and sex. Twenty-four patients met criteria for depression (16 major depression; 8 minor depression). There was a trend towards higher K/T ratios in depressed vs. non-depressed patients (45.6+/-20.0 micromol/mmol vs. 38.5+/-15.7 micromol/mmol, F=3.778, p=.055) when controlling for age, sex and tACS. Activation of IDO is associated with the severity of depressive symptoms among patients with CAD.
A Meta-Analysis of Cytokines In Alzheimer's Disease
Walter Swardfager, Krista L Lanctôt, Lana Rothenburg, Amy Wong, Jaclyn Cappell, Nathan Herrmann. Biol Psychiatry. 2010 Nov 15;68(10):930-41.
Background: Studies suggest that inflammation is involved in the neurodegenerative cascade leading to Alzheimer’s... more
Background: Studies suggest that inflammation is involved in the neurodegenerative cascade leading to Alzheimer’s disease (AD) pathology and symptoms. This study sought to quantitatively summarize the clinical cytokine data.
Methods: Original English language peer-reviewed studies measuring cytokine concentrations in AD and healthy control subjects were included. Mean (standard deviation) cytokine concentrations for AD and control subjects were extracted.
Results: Forty studies measuring peripheral blood cytokine concentrations and 14 measuring cerebrospinal fluid (CSF) cytokine concen- trations were included. In peripheral blood, there were significantly higher concentrations (weighted mean difference [95% confidence interval]) of interleukin (IL)-6 (2.86 [1.68, 4.04] pg/mL, p<.00001, N[AD/control subjects] 985/680, 14 studies), tumor necrosis factor (TNF)-alpha (3.25 [.76, 5.74] pg/mL, p=.01, N 680/447, 14 studies), IL-1beta (.55 [.32, .78] pg/mL, p<.00001, N 574/370, 10 studies), transforming growth factor (TGF)-beta (67.23 [28.62, 105.83] pg/mL, p=.0006, N 190/158, 5 studies), IL-12 (7.60 [5.58, 9.62] pg/mL, p<.00001, N 148/106, 5 studies), and IL-18 (15.82 [1.98, 29.66] pg/mL, p=.03, N 131/94, 4 studies) but not of IL-4, IL-8, IL-10, interferon-gamma, or C-reactive protein in AD subjects compared with control subjects. There were significantly higher concentrations of TGF-beta (7.81 [2.27, 13.35] pg/mL, p=.006, N 113/114, 5 studies) but not IL-6, TNF-alpha, and IL-1beta in the CSF of AD subjects compared with control subjects.
Conclusions: These results strengthen the clinical evidence that AD is accompanied by an inflammatory response, particularly higher peripheral concentrations of IL-6, TNF-alpha, IL-1beta, TGF-beta, IL-12 and IL-18 and higher CSF concentrations of TGF-beta.
Regulation of Innate Immunity During Trypanosoma cruzi Infection
Fredy SR Gutierrez
In: Control of Innate and Adaptive Immune Responses during Infectious Diseases. Springer. Edited by Julio Aliberti
Chagas Heart disease is caused by the infection with T. cruzi. The mechanisms of disease progression remain largely... more
Chagas Heart disease is caused by the infection with T. cruzi. The mechanisms of disease progression remain largely unknown although it has been reported that parasite persistence as well as the intensity of the inflammatory immune response are determinants for the clinical manifestations of the disease.
Through a long co-evolutionary history, both the human immune system and the pathogen have acquired diverse mechanisms to interact, guaranteeing their mutual survival. Even though inflammation is indispensable for host defense and tissue repair, when deregulated or disproportionate, it can contribute to continuous tissue injury, organ dysfunction, and disease. Thus, the immune system has acquired a great complexity in order to maintain the host’s integrity while it is able to arrest the proliferation of pathogens as soon as detected.
This chapter aims to review the regulatory mechanisms involved in the control of the effectors mechanisms of the innate immunity during experimental T. cruzi infection and Chagas disease. It provides a comprehensive revision of the immunologic mechanisms triggered by the interaction of the parasite and the host cells during acute phase of the infection, as well as the possible implications for the design of therapeutic or diagnostic approaches.
Download (.pdf) Medium-mediated DNA repair response after ionizing radiation is correlated with the increase of specific cytokines in human fibroblasts
B. Dieriks, W. De Vos, H. Derradji, S. Baatout and P. Van Oostveldt
Mutation Research – Fundamental and Molecular Mechanisms of Mutagenesis, 687(1-2), p40-48, 2010.
Radiation induced bystander effects, either protective or adverse, have been identified in a variety of cells and for... more Radiation induced bystander effects, either protective or adverse, have been identified in a variety of cells and for different endpoints. They are thought to arise from communication between cells through direct cell-cell contacts and via transmissible molecules secreted into the medium by targeted cells. We have investigated medium-mediated damage response in human dermal fibroblasts (HDF) after exposure to ionizing irradiation. We show that HDF experience an elevated level of double stranded DNA damage repair response when incubated with conditioned growth medium of irradiated cells. The magnitude of this response is much lower than observed for directly irradiated cells and is proportional to the radiation dose, as is its persistence across time. Since secretion of cytokines is one of the possible pathways linking targeted and non-targeted cells a multiplex analysis was performed. Four cytokines - IL6, IL8, MCP-1 and RANTES - were identified in the growth medium of irradiated cells after exposure to X-rays (2Gy). These cytokines were significantly upregulated and each cytokine showed differential upregulation kinetics. Finally we performed a functional analysis to see if IL6 and MCP-1 could induce gammaH2AX foci formation. IL6 caused a significant increase in spot occupancy compared to controls. Although only indicative MCP-1 appears to have the opposite effect as it caused a drop in spot occupancy. The combined addition of these two cytokines produced no significant response. Both IL6 and MCP-1 have an effect on the gammaH2AX spot occupancy possibly linking these cytokines to the bystander response.
Multiplexed profiling of secreted proteins for the detection of potential space biomarkers.
B. Dieriks(1), W. De Vos(1), M. Ghardi, M. Moreels, R. Hennekam, J. Broers, S. Baatout and P. Van Oostveldt.
Molecular Medicine Reports 4, 17-23, 2011.
(1equal contribution, first author).
Space travel exposes astronauts to a plethora of potentially detrimental conditions, such as cosmic radiation and... more Space travel exposes astronauts to a plethora of potentially detrimental conditions, such as cosmic radiation and microgravity. As both factors are hard to simulate on Earth, present knowledge remains limited. However, this knowledge is of vital importance, making space flight experiments a necessity for determining the biological effects and the underlying biochemical processes, especially when keeping future long-term interplanetary missions in mind. Instead of estimating the long-term effects, which usually implicate severe endpoints (e.g., cancer) and which are often difficult to attribute, research has shifted to finding representative biomarkers for rapid and sensitive detection of individual radiosensitivity. In this context, an appealing set of candidate markers is the group of secreted proteins, as they exert an intercellular signaling function and are easy to assess. We screened a subset of secreted proteins in cells exposed to space travel by means of multiplex bead array analysis. To determine the cell-specific signatures of the secreted molecules, we compared the conditioned medium of normal fibroblast cells to fibroblasts isolated from a patient with Hutchinson-Gilford Progeria syndrome, which are known to have a perturbed nuclear architecture and DNA damage response. Out of the 88 molecules screened, 20 showed a significant level increase or decrease, with a differential response to space conditions between the two cell types. Among the molecules that were retained, which may prove to be valuable biomarkers, are apolipoprotein C-III, plasminogen activator inhibitor type 1, β-2-microglobulin, ferritin, MMP-3, TIMP-1 and VEGF.
High content analysis of human fibroblast cell cultures after exposure to space radiation
B. Dieriks(1), W. De Vos(1), G. Meesen, K. Van Oostveldt, M. Ghardi, S. Baatout and P. Van Oostveldt.
Radiation Research 172(4), p423-436, 2009
(1equal contribution, first author)
Space travel imposes risks to human health, in large part by the increased radiation levels compared to those on... more Space travel imposes risks to human health, in large part by the increased radiation levels compared to those on Earth. To understand the effects of space radiation on humans, it is important to determine the underlying cellular mechanisms. While general dosimetry describes average radiation levels accurately, it says little about the actual physiological impact and does not provide biological information about individual cellular events. In addition, there is no information about the nature and magnitude of a systemic response through extra- and intercellular communication. To assess the stress response in human fibroblasts that were sent into space with the Foton-M3 mission, we have developed a pluralistic setup to measure DNA damage and inflammation response by combining global and local dosimetry, image cytometry and multiplex array technology, thereby maximizing the scientific output. We were able to demonstrate a significant increase in DNA double-strand breaks, determined by a twofold increase of the gamma-H2AX signal at the level of the single cell and a threefold up-regulation of the soluble signal proteins CCL5, IL-6, IL-8, beta-2 microglobulin and EN-RAGE, which are key players in the process of inflammation, in the growth medium.
Repeated exposure of human fibroblasts to ionizing radiation reveals an adaptive response that is not mediated by interleukin-6 or TGF-[beta]
B. Dieriks, W. De Vos, T. De Meyer, S. Baatout and P. Van Oostveldt
Mutation Research – Fundamental and Molecular Mechanisms of Mutagenesis, 715(1-2), 19-24, 2011.
Exposing cells to a low dose can protect them against a subsequent higher exposure. This phenomenon is known as... more Exposing cells to a low dose can protect them against a subsequent higher exposure. This phenomenon is known as adaptive response and is frequently observed in a variety of cells. Even though similarities are suspected with other non-targeted effects, such as bystander effects, the exact mechanism behind adaptive response is not fully clarified. In this study human primary fibroblasts were tested for their response to ionizing radiation (IR) after administrating a low priming dose (0.1-0.5Gy). Both the abundance of γH2AX as a marker for double-stranded breaks and the levels of cytokines, secreted in the medium, were monitored in time. Upon challenge, IR-primed cells showed modified γH2AX spot size distributions and altered repair kinetics, consistent with an adaptive response. In addition, 24h after priming with IR, four cytokines were significantly upregulated in the medium - GM-CSF (1.33×); IL6 (4.24×); IL8 (1.33×); TGF-β (1.46×). In order to mimick the protective effect of IR priming, we primed the cells with either IL6 or TGF-β. This did not elicit an altered γH2AX response as observed in IR-primed cells, indicating that the adaptive response in these primary fibroblasts is regulated in an IL-6 and TGF-β independent manner.
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Therapeutic regulation of cardiac fibroblast function: targeting stress-activated protein kinase pathways
by Neil Turner
NA Turner. Future Cardiol. 2011;7(5):673-91
Cardiac fibroblasts are key players in the myocardial remodeling process and respond to myocardial damage or... more Cardiac fibroblasts are key players in the myocardial remodeling process and respond to myocardial damage or dysfunction by adopting a myofibroblast phenotype and undergoing increased proliferation, migration, secretion of bioactive molecules and turnover of the extracellular matrix. Many of the key cellular responses of the heart to injury or stress are mediated via specific signaling cascades involving the stress-activated protein kinases (SAPKs). The SAPKs comprise the p38 MAPK and c-Jun N-terminal kinase families, both of which have been implicated in promoting myocardial damage and adverse cardiac remodeling. This article focuses on SAPK signaling cascades in the heart, with particular emphasis on their modulatory effects on cardiac fibroblast function, inflammation and fibrosis. It also describes current and future therapeutic strategies for inhibiting SAPKs in the myocardium. Understanding the role of SAPK signaling at the cellular level holds potential for developing novel therapies to ameliorate cardiac dysfunction in man.
Human cardiac fibroblasts express ICAM-1, E-selectin and CXC chemokines in response to proinflammatory cytokine stimulation
by Neil Turner
NA Turner et al. Int. J. Biochem. Cell Biol. 2011;43:1450-1458
Neutrophil attraction and adhesion to endothelial cells occurs via well defined mechanisms, yet the ability of other... more Neutrophil attraction and adhesion to endothelial cells occurs via well defined mechanisms, yet the ability of other cell types to express neutrophil-binding adhesion molecules is not well studied. Cardiac fibroblasts (CF) are a key cell type involved in repair of the infarcted myocardium, a scenario in which neutrophil recruitment is perceived to be detrimental. Here we determined the effects of proinflammatory cytokines on expression of neutrophil-binding adhesion molecules and neutrophil-attracting chemokines in CF cultured from multiple patients, and explored the underlying regulatory mechanisms. An adhesion molecule focused RT-PCR array identified 5 transcripts that were increased markedly in human CF treated with the proinflammatory cytokine interleukin-1 (IL-1, 10ng/ml, 6h); including intercellular cell adhesion molecule (ICAM-1) and E-selectin. Real-time RT-PCR verified the array data and immunoblotting confirmed cytokine-induced ICAM-1 and E-selectin protein expression. Treatment with a panel of pharmacological inhibitors identified the NF-κB pathway as mediating IL-1-induced ICAM-1 and E-selectin mRNA and protein expression. Additionally, E-selectin expression in human CF was markedly potentiated by the JNK inhibitor SP600125, but this was not observed when a more selective inhibitor ((L)-JNKI-1) was used, or in human vascular endothelial cells. IL-1 also stimulated CF to secrete the neutrophil chemoattractant CXCL8 via a p38- and NF-κB-dependent mechanism, as well as inducing CXCL1, CXCL2 and CXCL5 mRNA expression. In conclusion, human CF express neutrophil-binding adhesion molecules and neutrophil chemoattractants in response to proinflammatory cytokines suggesting that, in addition to EC, CF may play an important role in regulating neutrophil recruitment into the infarcted myocardium.
Acute Reversible Myocardial Depression associated with Sepsis
by 真 紺谷
Internal Medicine Vol.42: 60-65, 2003
A 30-year-old man was admitted to our hospital for left lobar pneumonia with septic shock.
Acute left-sided... more
A 30-year-old man was admitted to our hospital for left lobar pneumonia with septic shock.
Acute left-sided heart failure became evident as sepsis developed. Echocardiography revealed diffuse severe hypokinesis of the left ventricle (LV) and a pulmonary artery catheter showed Forrester subset II hemodynamics.
Along with amelioration of sepsis and decrease of the serum concentrations of tumor necrosis factor-a and interleukin-6, LV hypokinesis improved.
It is suggested that the patient's heart failure may have been due to functional depression of myocardial contractility resulting from a direct effect of the cytokines towards the cardiomyocytes, the so-called "septic myocardial depression". (Internal Medicine 42: 60-65, 2003)
High concentrations of reactive oxygen species in the BAL fluid are correlated with lung injury in rabbits after hemorrhagic shock and resuscitation.
Tasoulis MK, Livaditi O, Stamatakos M, Stefanaki C, Paneris P, Prigouris P, Flevari A, Goutas N, Vlachodimitropoulos D, Villiotou V, Douzinas EE.High concentrations of reactive oxygen species in the BAL fluid are correlated with lung injury in rabbits after hemorrhagic shock and resuscitation.Tohoku J Exp Med. 2009 Nov;219(3):193-9.
Modulatory effect of interleukin-1α on expression of structural matrix proteins, MMPs and TIMPs in human cardiac myofibroblasts: role of p38 MAP kinase
by Neil Turner
NA Turner et al. Matrix Biol. 2010;29:613-620
The proinflammatory cytokine interleukin-1 (IL-1) elicits catabolic effects on the myocardial extracellular matrix... more The proinflammatory cytokine interleukin-1 (IL-1) elicits catabolic effects on the myocardial extracellular matrix (ECM) early after myocardial infarction but there is little understanding of its direct effects on cardiac myofibroblasts (CMF), or the role of p38 mitogen-activated protein kinase (MAPK). We used a focused RT-PCR microarray to investigate the effects of IL-1α on expression of 41 ECM genes in CMF cultured from different patients, and explored regulation by p38 MAPK. IL-1α (10 ng/ml, 6h) had minimal effect on mRNA expression of structural ECM proteins, including collagens, laminins, fibronectin and vitronectin. However, it induced marked increases in expression of specific ECM proteases, including matrix metalloproteinases MMP-1 (collagenase-1), MMP-3 (stromelysin-1), MMP-9 (gelatinase-B) and MMP-10 (stromelysin-2). Conversely, IL-1α reduced mRNA and protein expression of ADAMTS1, a metalloproteinase that suppresses neovascularization. IL-1α increased expression of TIMP-1 slightly, but not TIMP-2. Data for MMP-1, MMP-2, MMP-3, MMP-9, MMP-10 and ADAMTS1 were confirmed by quantitative real-time RT-PCR. Tumor necrosis factor-alpha (TNFα), another important myocardial proinflammatory cytokine, did not alter expression of these metalloproteinases. IL-1α strongly activated the p38 MAPK pathway in human CMF. Pharmacological inhibitors of p38-α/β (SB203580) or p38-α/β/γ/δ (BIRB-0796) reduced MMP-3 and ADAMTS1 mRNA expression, but neither inhibitor affected MMP-9 levels. MMP-1 and MMP-10 expression were inhibited by BIRB-0796 but not SB203580, suggesting roles for p38-γ/δ. In summary, IL-1α induces a distinct pattern of ECM protein and protease expression in human CMF, in part regulated by distinct p38 MAPK subtypes, affirming the key role of IL-1α and CMF in post-infarction cardiac remodeling.
Interleukin 18 and coronary heart disease: Prospective study and systematic review
Jefferis BJ, Papacosta O, Owen CG, Wannamethee SG, Humphries SE, Woodward M, Lennon LT, Thomson A, Welsh P, Rumley A, Lowe GD, Whincup PH.
AIM: Previous studies suggest that circulating levels of interleukin-18 (IL-18) may be prospectively related to risk... more
AIM: Previous studies suggest that circulating levels of interleukin-18 (IL-18) may be prospectively related to risk of coronary heart disease (CHD) in the general population. We report new data from the largest prospective study to date, which are combined with data from all published prospective studies in a meta-analysis.
METHODS: We measured baseline IL-18 levels in stored serum samples of subjects from a case-control study nested within a prospective study of 5661 men aged 40-59 years recruited from general practices in 18 British towns in 1978-1980 and followed-up for up to 16 years (median time to event 8.4 years) for fatal CHD and non-fatal myocardial infarction (595 cases, 1238 controls).
RESULTS: IL-18 concentrations were strongly related to cigarette smoking, triglyceride, HDL-cholesterol (inversely) and to circulating levels of several inflammatory and haemostatic markers. Men in the top third of baseline IL-18 levels had an age-adjusted odds ratio (OR) for CHD of 1.55 (95% CI 1.21, 1.98) compared with those in the lowest third; this was reduced to 1.30 (95% CI 0.99, 1.69) after additional adjustment for vascular risk factors and 1.12 (95% CI 0.84, 1.49) after further adjustment for CRP and IL-6. In meta-analyses of CVD, associations (or effect sizes) were consistent between studies; RRs were 1.63 (95% CI 1.46, 1.82) after age adjustment, 1.39 (95% CI 1.24, 1.55) after additional risk factor adjustment and 1.34 (95% CI 1.17, 1.54) after additional adjustment for inflammatory markers.
CONCLUSIONS: Circulating IL-18 is prospectively and independently associated with CVD risk
Key words: Coronary heart disease; Epidemiology; Interleukin-
18; Cohort; Meta-analysis
Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors.
BACKGROUND:
Animal and clinical studies have revealed that focal peripheral nerve axon demyelination is... more
BACKGROUND:
Animal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats.
RESULTS:
Focal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon gamma-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1alpha (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca2+]i following exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-[R]) or its inactive enantiomer (CCR2 RA-[S]) by intraperitoneal (i.p.) injection. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia.
CONCLUSION:
These results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.
Chemokines and the Pathophysiology of Neuropathic Pain
Chemokines and chemokine receptors are widely expressed by cells of the immune and nervous systems. This review... more Chemokines and chemokine receptors are widely expressed by cells of the immune and nervous systems. This review focuses on our current knowledge concerning the role of chemokines in the pathophysiology of chronic pain syndromes. Injury- or disease-induced changes in the expression of diverse chemokines and their receptors have been demonstrated in the neural and nonneural elements of pain pathways. Under these circumstances, chemokines have been shown to modulate the electrical activity of neurons by multiple regulatory pathways including increases in neurotransmitter release through Ca-dependent mechanisms and transactivation of transient receptor channels. Either of these mechanisms alone, or in combination, may contribute to sustained excitability of primary afferent and secondary neurons within spinal pain pathways. Another manner in which chemokines may influence sustained neuronal excitability may be their ability to function as excitatory neurotransmitters within the peripheral and central nervous system. As is the case for traditional neurotransmitters, injury-induced up-regulated chemokines are found within synaptic vesicles. Chemokines released after depolarization of the cell membrane can then act on other chemokine receptor-bearing neurons, glia, or immune cells. Because up-regulation of chemokines and their receptors may be one of the mechanisms that directly or indirectly contribute to the development and maintenance of chronic pain, these molecules may then represent novel targets for therapeutic intervention in chronic pain states.