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Gao X, Jing D, Zhang Y, Zhu F, Yang Y, Zhou G. Unveiling the Role of GRK2: From Immune Regulation to Cancer Therapeutics. Mediators Inflamm 2025; 2025:8837640. [PMID: 40224487 PMCID: PMC11986179 DOI: 10.1155/mi/8837640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 02/04/2025] [Indexed: 04/15/2025] Open
Abstract
G protein-coupled receptors (GPCRs) represent humans' most prominent family of membrane proteins. In contrast, G protein-coupled receptor kinases (GRKs) play a pivotal role in the rapid desensitization of GPCRs. GRK2 is a particularly significant member of the GRK family. Recent studies have demonstrated that GRK2 primarily regulates immune cell function and homeostasis through receptor desensitization. Over the past decade, substantial progress has been made in elucidating the role of GRK2 in various human diseases. Notably, GRK2 is implicated in a range of autoimmune disorders, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), multiple sclerosis (MS), Sjögren's syndrome (SS), autoimmune myocarditis, hepatitis, and Graves' disease. Furthermore, emerging research has expanded our understanding of GRK2's involvement in cancer biology. Comprehensive investigations into the biological and pathological functions of GRK2 have facilitated the development of therapeutic strategies aimed at targeting the GRK2 signaling pathway in cancer, inflammation, and autoimmune diseases. Promising results have been observed with targeted biologics in preclinical and clinical trials. This review aims to elucidate the multifaceted role of GRK2 in immune function, autoimmune diseases, and cancer to uncover the remaining complexities associated with this kinase. A thorough understanding of GRK2 may position it as a potent therapeutic target in treating inflammation and cancer.
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Affiliation(s)
- Xizhuang Gao
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining 272000, Shandong, China
| | - Dehuai Jing
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining 272000, Shandong, China
| | - Yaowen Zhang
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining 272000, Shandong, China
| | - Fengqin Zhu
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining 272000, Shandong, China
| | - Yonghong Yang
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining 272000, Shandong, China
| | - Guangxi Zhou
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining 272000, Shandong, China
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Chen G, Jin Y, Chu C, Zheng Y, Yang C, Chen Y, Zhu X. A cross-tissue transcriptome-wide association study reveals GRK4 as a novel susceptibility gene for COPD. Sci Rep 2024; 14:28438. [PMID: 39558015 PMCID: PMC11574126 DOI: 10.1038/s41598-024-80122-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/15/2024] [Indexed: 11/20/2024] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disorder with environmental factors being the primary risk determinants. However, genetic factors also substantially contribute to the susceptibility and progression of COPD. Although genome-wide association studies (GWAS) have identified several loci associated with COPD susceptibility, the specific pathogenic genes underlying these loci, along with their biological functions and roles within regulatory networks, remain unclear. This lack of clarity constrains our ability to achieve a deeper understanding of the genetic basis of COPD. This study leveraged the FinnGen R11 genetic dataset, comprising 21,617 cases and 372,627 controls, along with GTEx V8 eQTLs data to conduct a cross-tissue transcriptome-wide association study (TWAS). Initially, we performed a cross-tissue TWAS analysis using the Unified Test for Molecular Signatures (UTMOST), followed by validation of the UTMOST findings in single tissues using the Functional Summary-based Imputation (FUSION) method and conditional and joint (COJO) analyses of the identified genes. Subsequently, candidate susceptibility genes were screened using Multi-marker Analysis of Genomic Annotation (MAGMA). The causal relationship between these candidate genes and COPD was further evaluated through summary data-based Mendelian randomization (SMR), colocalization analysis, and Mendelian randomization (MR). Additionally, the identified results were validated against the COPD dataset in the GWAS Catalog (GCST90399694). GeneMANIA was employed to further explore the functional significance of these susceptibility genes. In the cross-tissue TWAS analysis (UTMOST), we identified 17 susceptibility genes associated with COPD. Among these, a novel susceptibility gene, G protein-coupled receptor kinase 4 (GRK4), was validated through single-tissue TWAS (FUSION) and MAGMA analyses, with further confirmation via SMR, MR, and colocalization analyses. Moreover, GRK4 was validated in an independent dataset. This study identifies GRK4 as a potential novel susceptibility gene for COPD, which may influence disease risk by exacerbating inflammatory responses. The findings address gaps in previous single-tissue GWAS studies, revealing consistent expression and potential function of GRK4 across different tissues. However, considering the study's limitations, further investigation and validation of GRK4's role in COPD are warranted.
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Affiliation(s)
- Guanglei Chen
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
| | - Yaxian Jin
- The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550000, Guizhou, China
| | - Cancan Chu
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
| | - Yuhao Zheng
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
| | - Changfu Yang
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
| | - Yunzhi Chen
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
| | - Xing Zhu
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China.
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Pilipović I, Stojić-Vukanić Z, Leposavić G. Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis. Pharmacol Ther 2023; 243:108358. [PMID: 36804434 DOI: 10.1016/j.pharmthera.2023.108358] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 02/03/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023]
Abstract
This review summarizes recent findings related to the role of the sympathetic nervous system (SNS) in pathogenesis of multiple sclerosis (MS) and its commonly used experimental model - experimental autoimmune encephalomyelitis (EAE). They indicate that noradrenaline, the key end-point mediator of the SNS, acting through β-adrenoceptor, has a contributory role in the early stages of MS/EAE development. This stage is characterized by the SNS hyperactivity (increased release of noradrenaline) reflecting the net effect of different factors, such as the disease-associated inflammation, stress, vitamin D hypovitaminosis, Epstein-Barr virus infection and dysbiosis. Thus, the administration of propranolol, a non-selective β-adrenoceptor blocker, readily crossing the blood-brain barrier, to experimental rats before the autoimmune challenge and in the early (preclinical/prodromal) phase of the disease mitigates EAE severity. This phenomenon has been ascribed to the alleviation of neuroinflammation (due to attenuation of primarily microglial activation/proinflammatory functions) and the diminution of the magnitude of the primary CD4+ T-cell autoimmune response (the effect associated with impaired autoantigen uptake by antigen presenting cells and their migration into draining lymph nodes). The former is partly related to breaking of the catecholamine-dependent self-amplifying microglial feed-forward loop and the positive feedback loop between microglia and the SNS, leading to down-regulation of the SNS hyperactivity and its enhancing influence on microglial activation/proinflammatory functions and the magnitude of autoimmune response. The effects of propranolol are shown to be more prominent in male EAE animals, the phenomenon important as males (like men) are likely to develop clinically more severe disease. Thus, these findings could serve as a firm scientific background for formulation of a new sex-specific immune-intervention strategy for the early phases of MS (characterized by the SNS hyperactivity) exploiting anti-(neuro)inflammatory and immunomodulatory properties of propranolol and other relatively cheap and safe adrenergic drugs with similar therapeutic profile.
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Affiliation(s)
- Ivan Pilipović
- Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia
| | - Zorica Stojić-Vukanić
- University of Belgrade-Faculty of Pharmacy, Department of Microbiology and Immunology, Belgrade, Serbia
| | - Gordana Leposavić
- University of Belgrade-Faculty of Pharmacy, Department of Pathobiology, Belgrade, Serbia.
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Autoimmune autonomic nervous system imbalance and conditions: Chronic fatigue syndrome, fibromyalgia, silicone breast implants, COVID and post-COVID syndrome, sick building syndrome, post-orthostatic tachycardia syndrome, autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants. Clin Exp Rheumatol 2023; 22:103230. [PMID: 36347462 DOI: 10.1016/j.autrev.2022.103230] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Chronic fatigue syndrome (CFS), fibromyalgia, silicone breast implants syndrome (SBIs), COVID and post-COVID syndrome (PCS), sick building syndrome (SBS), post-orthostatic tachycardia syndrome (POTS), autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants (ASIA) are frequently accompanied by clinical symptoms characteristic for dysautonomia: severe fatigue, dizziness, fogginess, memory loss, dry mouth and eyes, hearing dysfunction, tachycardia etc. The recent discovery of an imbalance of autoantibodies against G protein-coupled receptors (GPCR) in some autoimmune diseases, post-COVID syndrome, SBIs allowed researchers to assume the novel mechanism in these conditions - autoimmune autonomic nervous system imbalance. In this review, all data published on an imbalance of autoantibodies against GPCR, clinical symptoms and pathogenic mechanisms in CFS, Fibromyalgia, SBIs, COVID and PCS, SBS, POTS, and some autoimmune diseases were analyzed. Possible criteria to diagnose the autoimmune autonomic nervous system imbalance were created.
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Malkova AM, Shoenfeld Y. WITHDRAWN: Autoimmune autonomic nervous system imbalance and conditions: Chronic fatigue syndrome, fibromyalgia, silicone breast implants, COVID and post-COVID syndrome, sick building syndrome, post-orthostatic tachycardia syndrome, autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants. Autoimmun Rev 2022:103231. [PMID: 36356798 DOI: 10.1016/j.autrev.2022.103231] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022]
Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.autrev.2022.103230. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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Affiliation(s)
- A M Malkova
- Zabludowicz Center of autoimmunity, Sheba Medical Center, Tel Hashomer, Israel.
| | - Y Shoenfeld
- Zabludowicz Center of autoimmunity, Sheba Medical Center, Tel Hashomer, Israel
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Cheng H, Guo P, Su T, Jiang C, Zhu Z, Wei W, Zhang L, Wang Q. G protein-coupled receptor kinase type 2 and β-arrestin2: Key players in immune cell functions and inflammation. Cell Signal 2022; 95:110337. [PMID: 35461901 DOI: 10.1016/j.cellsig.2022.110337] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 04/15/2022] [Accepted: 04/15/2022] [Indexed: 02/07/2023]
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Cheng J, Lucas PC, McAllister-Lucas LM. Canonical and Non-Canonical Roles of GRK2 in Lymphocytes. Cells 2021; 10:cells10020307. [PMID: 33546162 PMCID: PMC7913175 DOI: 10.3390/cells10020307] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 12/18/2022] Open
Abstract
G protein-coupled receptor kinase 2 (GRK2) is emerging as a key integrative signaling node in a variety of biological processes ranging from cell growth and proliferation to migration and chemotaxis. As such, GRK2 is now implicated as playing a role in the molecular pathogenesis of a broad group of diseases including heart failure, cancer, depression, neurodegenerative disease, and others. In addition to its long-known canonical role in the phosphorylation and desensitization of G protein-coupled receptors (GPCRs), recent studies have shown that GRK2 also modulates a diverse array of other molecular processes via newly identified GRK2 kinase substrates and via a growing number of protein-protein interaction binding partners. GRK2 belongs to the 7-member GRK family. It is a multidomain protein containing a specific N-terminal region (referred to as αN), followed by a regulator of G protein signaling homology (RH) domain, an AGC (Protein kinase A, G, C serine/threonine kinase family) kinase domain, and a C-terminal pleckstrin homology (PH) domain. GPCRs mediate the activity of many regulators of the immune system such as chemokines and leukotrienes, and thus GRK proteins may play key roles in modulating the lymphocyte response to these factors. As one of the predominant GRK family members expressed in immune cells, GRK2's canonical and noncanonical actions play an especially significant role in normal immune cell function as well as in the development and progression of disorders of the immune system. This review summarizes our current state of knowledge of the roles of GRK2 in lymphocytes. We highlight the diverse functions of GRK2 and discuss how ongoing investigation of GRK2 in lymphocytes may inform the development of new therapies for diseases associated with lymphocyte dysregulation.
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Affiliation(s)
- Jing Cheng
- Division of Hematology-Oncology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA;
- Correspondence:
| | - Peter C. Lucas
- Divisions of Molecular Genomic Pathology and Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA;
- UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
| | - Linda M. McAllister-Lucas
- Division of Hematology-Oncology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA;
- UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
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Chhatar S, Lal G. Role of adrenergic receptor signalling in neuroimmune communication. CURRENT RESEARCH IN IMMUNOLOGY 2021; 2:202-217. [PMID: 35492402 PMCID: PMC9040148 DOI: 10.1016/j.crimmu.2021.11.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 11/11/2021] [Accepted: 11/17/2021] [Indexed: 11/17/2022] Open
Abstract
Neuroimmune communication plays a crucial role in maintaining homeostasis and promptly responding to any foreign insults. Sympathetic nerve fibres are innervated into all the lymphoid organs (bone marrow, thymus, spleen, and lymph nodes) and provide a communication link between the central nervous system (CNS) and ongoing immune response in the tissue microenvironment. Neurotransmitters such as catecholamines (epinephrine and norepinephrine) bind to adrenergic receptors present on most immune and non-immune cells, establish a local neuroimmune-communication system, and help regulate the ongoing immune response. The activation of these receptors varies with the type of receptor-activated, target cell, the activation status of the cells, and timing of activation. Activating adrenergic receptors, specifically β-adrenergic signalling in immune cells leads to activation of the cAMP-PKA pathway or other non-canonical pathways. It predominantly leads to immune suppression such as inhibition of IL-2 secretion and a decrease in macrophages phagocytosis. This review discusses the expression of different adrenergic receptors in various immune cells, signalling, and how it modulates immune cell function and contributes to health and diseases. Understanding the neuroimmune communication through adrenergic receptor signalling in immune cells could help to design better strategies to control inflammation and autoimmunity.
Primary and secondary lymphoid organs are innervated with sympathetic nerve fibres. Adrenergic receptor expression on immune and non-immune cells establishes a local neuroimmune communication system. Adrenergic receptor signalling in immune cells controls the differentiation and function of various immune cells. Modulating adrenergic receptor signalling with a specific agonist or antagonist also affect the immune response.
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Affiliation(s)
| | - Girdhari Lal
- Corresponding author. National Centre for Cell Science, NCCS Complex, Ganeshkhind, Pune, MH-411007, India.
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Habek M. Immune and autonomic nervous system interactions in multiple sclerosis: clinical implications. Clin Auton Res 2019; 29:267-275. [PMID: 30963343 DOI: 10.1007/s10286-019-00605-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 03/28/2019] [Indexed: 12/25/2022]
Abstract
Multiple sclerosis is characterized by a wide spectrum of clinical manifestations, among which dysfunction of the autonomic nervous system represents an important cause of multiple sclerosis-related disability. The aim of this review is to provide an overview of autonomic dysfunction in people with multiple sclerosis, and to discuss the interactions between the immune and autonomic nervous systems and the effects of these interactions on various aspects of multiple sclerosis. Autonomic dysfunction in people with multiple sclerosis can be demonstrated clinically and on a molecular level. Clinically, it can be demonstrated by measuring autonomic symptoms with the Composite Autonomic Symptom Score (COMPASS-31), and neurophysiologically, with different autonomic nervous system tests. Both symptomatic and objectively determined autonomic dysfunction can be associated with increased risk of multiple sclerosis disease activity. Further supporting these clinical observations are molecular changes in immune cells. Changes in the sympathetic autonomic system, such as different expression of dopaminergic and adrenergic receptors on immune cells, or modulation of the cholinergic anti-inflammatory pathway over different subunits of the nicotinic acetylcholine receptor in the peripheral immune system, may mediate different effects on multiple sclerosis disease activity.
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Affiliation(s)
- Mario Habek
- Department of Neurology, Referral Center for Autonomic Nervous System Disorders, University Hospital Center Zagreb, Kišpatićeva 12, 10000, Zagreb, Croatia. .,School of Medicine, University of Zagreb, Zagreb, Croatia.
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10
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Palikhe S, Ohashi W, Sakamoto T, Hattori K, Kawakami M, Andoh T, Yamazaki H, Hattori Y. Regulatory Role of GRK2 in the TLR Signaling-Mediated iNOS Induction Pathway in Microglial Cells. Front Pharmacol 2019; 10:59. [PMID: 30778300 PMCID: PMC6369205 DOI: 10.3389/fphar.2019.00059] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 01/18/2019] [Indexed: 12/31/2022] Open
Abstract
G protein-coupled receptor kinase 2 (GRK2) is a ubiquitous member of the GRK family that restrains cellular activation by G protein-coupled receptor (GPCR) phosphorylation leading to receptor desensitization and internalization, but has been identified to regulate a variety of signaling molecules, among which may be associated with inflammation. In this study, we attempted to establish the regulatory role of GRK2 in the Toll-like receptor (TLR) signaling pathway for inducible nitric oxide synthase (iNOS) expression in microglial cells. When mouse MG6 cells were stimulated with the TLR4 ligands lipopolysaccharide (LPS) and paclitaxel, we found that interferon regulatory factor 1 (IRF1) protein expression and activation was upregulated, transcription of interferon-β (IFN-β) was accelerated, induction/activation of STAT1 and activation of STAT3 were promoted, and subsequently iNOS expression was upregulated. The ablation of GRK2 by small interfering RNAs (siRNAs) not only eliminated TLR4-mediated upregulation of IRF1 protein expression and nuclear translocation but also suppressed the activation of the STAT pathway, resulting in negating the iNOS upregulation. The TLR3-mediated changes in IRF1 and STAT1/3, leading to iNOS induction, were also abrogated by siRNA knockdown of GRK2. Furthermore, transfection of GRK2 siRNA blocked the exogenous IFN-β supplementation-induced increases in phosphorylation of STAT1 as well as STAT3 and abrogated the augmentation of iNOS expression in the presence of exogenous IFN-β. Taken together, our results show that GRK2 regulates the activation of IRF1 as well as the activation of the STAT pathway, leading to upregulated transcription of iNOS in activated microglial cells. Modulation of the TLR signaling pathway via GRK2 in microglia may be a novel therapeutic target for treatment of neuroinflammatory disorders.
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Affiliation(s)
- Sailesh Palikhe
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Wakana Ohashi
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Takuya Sakamoto
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Kohshi Hattori
- Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Masaaki Kawakami
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Tsugunobu Andoh
- Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Hiromi Yamazaki
- Faculty of Nursing Science, Tsuruga Nursing University, Tsuruga, Japan
| | - Yuichi Hattori
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
- The Research Institute of Cancer Prevention, Health Sciences University of Hokkaido, Tobetsu, Japan
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Wu L, Tai Y, Hu S, Zhang M, Wang R, Zhou W, Tao J, Han Y, Wang Q, Wei W. Bidirectional Role of β2-Adrenergic Receptor in Autoimmune Diseases. Front Pharmacol 2018; 9:1313. [PMID: 30538630 PMCID: PMC6277539 DOI: 10.3389/fphar.2018.01313] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 10/29/2018] [Indexed: 12/20/2022] Open
Abstract
Disorder of the sympathetic nervous system (SNS) is closely related to the pathogenesis of various autoimmune diseases (ADs). Catecholamine triggered beta2-adrenergic receptor (β2-AR) signaling is important in creating a bidirectional response in the progression of ADs due to factors including diverse expression patterns, single nucleotide polymorphisms (SNPs), biased signals, and desensitization of β2-AR, as well as different subtypes of Gα binding to β2-AR. In this review, we summarize the actions of β2-AR signaling in regulating the functions of immunocytes and in the pathogenesis of ADs, and the application of β2-AR agonists or antagonists in treating major types of ADs is also discussed. We suggest that restoring the immune balance via a soft regulation of the expression or activation of β2-AR is one of the promising therapeutic strategies for systematic ADs.
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Affiliation(s)
- Li Wu
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Yu Tai
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Shanshan Hu
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Mei Zhang
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Rui Wang
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Weijie Zhou
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Juan Tao
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Yongsheng Han
- Department of Emergency Medicine, The First Affiliated Hospital, University of Science and Technology of China, Hefei, China
| | - Qingtong Wang
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Wei Wei
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
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Kawakami M, Hattori M, Ohashi W, Fujimori T, Hattori K, Takebe M, Tomita K, Yokoo H, Matsuda N, Yamazaki M, Hattori Y. Role of G protein-coupled receptor kinase 2 in oxidative and nitrosative stress-related neurohistopathological changes in a mouse model of sepsis-associated encephalopathy. J Neurochem 2018; 145:474-488. [PMID: 29500815 DOI: 10.1111/jnc.14329] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 02/20/2018] [Accepted: 02/22/2018] [Indexed: 11/30/2022]
Abstract
Sepsis-associated encephalopathy (SAE), characterized as diffuse brain dysfunction and neurological manifestations secondary to sepsis, is a common complication in critically ill patients and can give rise to poor outcome, but understanding the molecular basis of this disorder remains a major challenge. Given the emerging role of G protein-coupled receptor 2 (GRK2), first identified as a G protein-coupled receptor (GPCR) regulator, in the regulation of non-G protein-coupled receptor-related molecules contributing to diverse cellular functions and pathology, including inflammation, we tested the hypothesis that GRK2 may be linked to the neuropathogenesis of SAE. When mouse MG6 microglial cells were challenged with lipopolysaccharide (LPS), GRK2 cytosolic expression was highly up-regulated. The ablation of GRK2 by small interfering RNAs (siRNAs) prevented an increase in intracellular reactive oxygen species generation in LPS-stimulated MG6 cells. Furthermore, the LPS-induced up-regulation of inducible nitric-oxide synthase expression and increase in nitric oxide production were negated by GRK2 inhibitor or siRNAs. However, GRK2 inhibition was without effect on overproduction of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β in LPS-stimulated MG cells. In mice with cecal ligation and puncture-induced sepsis, treatment with GRK2 inhibitor reduced high levels of oxidative and nitrosative stress in the mice brains, where GRK2 expression was up-regulated, alleviated neurohistological damage observed in cerebral cortex sections, and conferred a significant survival advantage to CLP mice. Altogether, these results uncover the novel role for GRK2 in regulating cellular oxidative and nitrosative stress during inflammation and suggest that GRK2 may have a potential as an intriguing therapeutic target to prevent or treat SAE.
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Affiliation(s)
- Masaaki Kawakami
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.,Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Mizuki Hattori
- Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Wakana Ohashi
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Toshio Fujimori
- Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Kohshi Hattori
- Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Mariko Takebe
- Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Kengo Tomita
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Hiroki Yokoo
- Department of Health and Nutritional Sciences, Faculty of Health Promotional Sciences, Tokoha University, Hamamatsu, Japan
| | - Naoyuki Matsuda
- Department of Emergency and Critical Care Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuaki Yamazaki
- Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Yuichi Hattori
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
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Cardiovascular Autonomic Dysfunction: Link Between Multiple Sclerosis Osteoporosis and Neurodegeneration. Neuromolecular Med 2018; 20:37-53. [DOI: 10.1007/s12017-018-8481-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 02/06/2018] [Indexed: 12/19/2022]
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14
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15
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Guccione M, Ettari R, Taliani S, Da Settimo F, Zappalà M, Grasso S. G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitors: Current Trends and Future Perspectives. J Med Chem 2016; 59:9277-9294. [PMID: 27362616 DOI: 10.1021/acs.jmedchem.5b01939] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
G-protein-coupled receptor kinase 2 (GRK2) is a G-protein-coupled receptor kinase that is ubiquitously expressed in many tissues and regulates various intracellular mechanisms. The up- or down-regulation of GRK2 correlates with several pathological disorders. GRK2 plays an important role in the maintenance of heart structure and function; thus, this kinase is involved in many cardiovascular diseases. GRK2 up-regulation can worsen cardiac ischemia; furthermore, increased kinase levels occur during the early stages of heart failure and in hypertensive subjects. GRK2 up-regulation can lead to changes in the insulin signaling cascade, which can translate to insulin resistance. Increased GRK2 levels also correlate with the degree of cognitive impairment that is typically observed in Alzheimer's disease. This article reviews the most potent and selective GRK2 inhibitors that have been developed. We focus on their mechanism of action, inhibition profile, and structure-activity relationships to provide insight into the further development of GRK2 inhibitors as drug candidates.
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Affiliation(s)
- Manuela Guccione
- Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università degli Studi di Messina , Viale Annunziata, 98168 Messina, Italy
| | - Roberta Ettari
- Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università degli Studi di Messina , Viale Annunziata, 98168 Messina, Italy
| | - Sabrina Taliani
- Dipartimento di Farmacia, Università di Pisa , Via Bonanno Pisano 6, 56126 Pisa, Italy
| | - Federico Da Settimo
- Dipartimento di Farmacia, Università di Pisa , Via Bonanno Pisano 6, 56126 Pisa, Italy
| | - Maria Zappalà
- Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università degli Studi di Messina , Viale Annunziata, 98168 Messina, Italy
| | - Silvana Grasso
- Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università degli Studi di Messina , Viale Annunziata, 98168 Messina, Italy
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16
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Zhou Y, Li RJ, Li M, Liu X, Zhu HY, Ju Z, Miao X, Xu GY. Overexpression of GRK6 attenuates neuropathic pain via suppression of CXCR2 in rat dorsal root ganglion. Mol Pain 2016; 12:12/0/1744806916646381. [PMID: 27145805 PMCID: PMC4956389 DOI: 10.1177/1744806916646381] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 03/29/2016] [Indexed: 12/14/2022] Open
Abstract
G protein-coupled kinase (GRK) 6 is a member of the GRK family that mediates agonist-induced desensitization and signaling of G protein-coupled receptors (GPCRs), thus involving in a wide variety of processes including inflammation and nociception. Recent studies have indicated that chemokines play an important role in chronic pain via increased expression of respective GPCRs. This study was designed to investigate the role of GRK6 and its interaction with substrate chemokine receptors in dorsal root ganglion (DRG) in a rat model of neuropathic pain induced by chronic constriction injury (CCI). Following induction of CCI, GRK6 expression was significantly downregulated in rat DRGs at L4-L6 segments. Overexpression of GRK6 using lentiviral-mediated production strategy via sciatic nerve injection markedly attenuated mechanical allodynia and thermal hyperalgesia in CCI rats. Overexpression of GRK6 also drastically reversed the hyperexcitability of DRG neurons innervating the hind paw and suppressed the enhanced expression of CXCR2 in DRGs of CCI rats. In addition, co-immunoprecipitation, immunofluorescence, and correlation analysis supported the interaction between GRK6 and CXCR2. These results suggest that GRK6 might be a key molecular involved in peripheral mechanism of neuropathic pain and that overexpression of GRK6 might be a potential strategy for treatment for neuropathic pain through inhibition of CXCR2 signal pathway.
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Affiliation(s)
- Yuan Zhou
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, P.R. China Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Rong-Ji Li
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, P.R. China
| | - Meng Li
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, P.R. China
| | - Xuelian Liu
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, P.R. China
| | - Hong-Yan Zhu
- Center for Translational Medicine, Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, P.R. China
| | - Zhong Ju
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, P.R. China
| | - Xiuhua Miao
- Center for Translational Medicine, Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, P.R. China
| | - Guang-Yin Xu
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, P.R. China Center for Translational Medicine, Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, P.R. China
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17
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Impaired Neurovisceral Integration of Cardiovascular Modulation Contributes to Multiple Sclerosis Morbidities. Mol Neurobiol 2016; 54:362-374. [DOI: 10.1007/s12035-015-9599-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 12/01/2015] [Indexed: 12/16/2022]
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18
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Autonomic dysfunction, immune regulation, and multiple sclerosis. Clin Auton Res 2015; 26:23-31. [DOI: 10.1007/s10286-015-0325-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 11/01/2015] [Indexed: 01/28/2023]
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19
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Sternberg Z. Genetic, Epigenetic, and Environmental Factors Influencing Neurovisceral Integration of Cardiovascular Modulation: Focus on Multiple Sclerosis. Neuromolecular Med 2015; 18:16-36. [PMID: 26502224 DOI: 10.1007/s12017-015-8375-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 10/19/2015] [Indexed: 12/31/2022]
Abstract
Thought to be an autoimmune inflammatory CNS disease, multiple sclerosis (MS) involves multiple pathologies with heterogeneous clinical presentations. An impaired neurovisceral integration of cardiovascular modulation, indicated by sympathetic and parasympathetic autonomic nervous system (ANS) dysfunction, is among common MS clinical presentations. ANS dysfunction could not only enhance MS inflammatory and neurodegenerative processes, but can also lead to clinical symptoms such as depression, fatigue, sleep disorder, migraine, osteoporosis, and cerebral hemodynamic impairments. Therefore, factors influencing ANS functional activities, in one way or another, will have a significant impact on MS disease course. This review describes the genetic and epigenetic factors, and their interactions with a number of environmental factors contributing to the neurovisceral integration of cardiovascular modulation, with a focus on MS. Future studies should investigate the improvement in cardiovascular ANS function, as a strategy for preventing and minimizing MS-related morbidities, and improving patients' quality of life.
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20
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Inhibition of G-Protein βγ Signaling Decreases Levels of Messenger RNAs Encoding Proinflammatory Cytokines in T Cell Receptor-Stimulated CD4(+) T Helper Cells. J Mol Signal 2015; 10:1. [PMID: 27095999 PMCID: PMC4831316 DOI: 10.5334/1750-2187-10-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background: Inhibition of G-protein βγ (Gβγ) signaling was found previously to enhance T cell receptor (TCR)-stimulated increases in interleukin 2 (IL-2) mRNA in CD4+ T helper cells, suggesting that Gβγ might be a useful drug target for treating autoimmune diseases, as low dose IL-2 therapy can suppress autoimmune responses. Because IL-2 may counteract autoimmunity in part by shifting CD4+ T helper cells away from the Type 1 T helper cell (TH1) and TH17 subtypes towards the TH2 subtype, the purpose of this study was to determine if blocking Gβγ signaling affected the balance of TH1, TH17, and TH2 cytokine mRNAs produced by CD4+ T helper cells. Methods: Gallein, a small molecule inhibitor of Gβγ, and siRNA-mediated silencing of the G-protein β1 subunit (Gβ1) were used to test the effect of blocking Gβγ on mRNA levels of cytokines in primary human TCR-stimulated CD4+ T helper cells. Results: Gallein and Gβ1 siRNA decreased interferon-γ (IFN-γ) and IL-17A mRNA levels in TCR-stimulated CD4+ T cells grown under TH1-promoting conditions. Inhibiting Gβγ also decreased mRNA levels of STAT4, which plays a positive role in TH1 differentiation and IL-17A production. Moreover, mRNA levels of the STAT4-regulated TH1-associated proteins, IL-18 receptor β chain (IL-18Rβ), mitogen-activated protein kinase kinase kinase 8 (MAP3K8), lymphocyte activation gene 3 (LAG-3), natural killer cell group 7 sequence (NKG7), and oncostatin M (OSM) were also decreased upon Gβγ inhibition. Gallein also increased IL-4, IL-5, IL-9, and IL-13 mRNA levels in TCR-stimulated memory CD4+ T cells grown in TH2-promoting conditions. Conclusions: Inhibiting Gβγ to produce these shifts in cytokine mRNA production might be beneficial for patients with autoimmune diseases such as rheumatoid arthritis (RA), Crohn’s disease (CD), psoriasis, multiple sclerosis (MS), and Hashimoto’s thyroiditis (HT), in which both IFN-γ and IL-17A are elevated.
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21
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Molecular mechanisms underlying β-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. Int J Mol Sci 2015; 16:5635-65. [PMID: 25768345 PMCID: PMC4394497 DOI: 10.3390/ijms16035635] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Revised: 02/13/2015] [Accepted: 03/04/2015] [Indexed: 01/01/2023] Open
Abstract
Cross-talk between the sympathetic nervous system (SNS) and immune system is vital for health and well-being. Infection, tissue injury and inflammation raise firing rates of sympathetic nerves, increasing their release of norepinephrine (NE) in lymphoid organs and tissues. NE stimulation of β2-adrenergic receptors (ARs) in immune cells activates the cAMP-protein kinase A (PKA) intracellular signaling pathway, a pathway that interfaces with other signaling pathways that regulate proliferation, differentiation, maturation and effector functions in immune cells. Immune-SNS cross-talk is required to maintain homeostasis under normal conditions, to develop an immune response of appropriate magnitude after injury or immune challenge, and subsequently restore homeostasis. Typically, β2-AR-induced cAMP is immunosuppressive. However, many studies report actions of β2-AR stimulation in immune cells that are inconsistent with typical cAMP-PKA signal transduction. Research during the last decade in non-immune organs, has unveiled novel alternative signaling mechanisms induced by β2-AR activation, such as a signaling switch from cAMP-PKA to mitogen-activated protein kinase (MAPK) pathways. If alternative signaling occurs in immune cells, it may explain inconsistent findings of sympathetic regulation of immune function. Here, we review β2-AR signaling, assess the available evidence for alternative signaling in immune cells, and provide insight into the circumstances necessary for "signal switching" in immune cells.
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22
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Cosentino M, Zaffaroni M, Marino F. Levels of mRNA for dopaminergic receptor D₅ in circulating lymphocytes may be associated with subsequent response to interferon-β in patients with multiple sclerosis. J Neuroimmunol 2014; 277:193-6. [PMID: 25468276 DOI: 10.1016/j.jneuroim.2014.10.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 10/15/2014] [Accepted: 10/24/2014] [Indexed: 01/10/2023]
Abstract
Interferon (IFN)-β is among the first-line therapies for multiple sclerosis (MS), however the clinical response varies among individuals, and early identification of responders and non-responders would be of critical importance. Here we show that before treatment circulating lymphocytes of MS patients who will respond to IFN-β have higher mRNA levels for the D1-like dopaminergic receptor (DR) D5 in comparison to cells from those who will not respond. Lymphocyte DR D5 is reduced in MS and IFN-β restores their expression and responsiveness. DR D5 mRNA levels in circulating lymphocytes might represent an early marker of response to IFN-β in MS patients.
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Affiliation(s)
- Marco Cosentino
- Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy.
| | - Mauro Zaffaroni
- Multiple Sclerosis Center, Hospital 'S. Antonio Abate', Gallarate, VA, Italy
| | - Franca Marino
- Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy
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23
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Daniele S, Trincavelli ML, Fumagalli M, Zappelli E, Lecca D, Bonfanti E, Campiglia P, Abbracchio MP, Martini C. Does GRK–β arrestin machinery work as a “switch on” for GPR17-mediated activation of intracellular signaling pathways? Cell Signal 2014; 26:1310-25. [DOI: 10.1016/j.cellsig.2014.02.016] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 02/27/2014] [Accepted: 02/27/2014] [Indexed: 12/13/2022]
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24
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Sorriento D, Fusco A, Ciccarelli M, Rungi A, Anastasio A, Carillo A, Dorn GW, Trimarco B, Iaccarino G. Mitochondrial G protein coupled receptor kinase 2 regulates proinflammatory responses in macrophages. FEBS Lett 2013; 587:3487-94. [PMID: 24036448 DOI: 10.1016/j.febslet.2013.09.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 08/26/2013] [Accepted: 09/02/2013] [Indexed: 01/09/2023]
Abstract
G-protein-coupled receptor kinase 2 (GRK2) levels are elevated in inflammation but its role is not clear yet. Here we show that GRK2 expression is dependent on NFκB transcriptional activity. In macrophages, LPS induces GRK2 accumulation in mitochondria increasing biogenesis. The overexpression of the carboxy-terminal domain of GRK2 (βARK-ct), known to displace GRK2 from plasma membranes, induces earlier localization of GRK2 to mitochondria in response to LPS leading to increased mt-DNA transcription and reduced ROS production and cytokine expression. Our study shows the relevance of GRK2 subcellular localization in macrophage biology and its potential therapeutic properties in inflammation.
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Affiliation(s)
- D Sorriento
- Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy
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25
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Decreased expression and role of GRK6 in spinal cord of rats after chronic constriction injury. Neurochem Res 2013; 38:2168-79. [PMID: 23979726 DOI: 10.1007/s11064-013-1125-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2012] [Revised: 07/17/2013] [Accepted: 07/31/2013] [Indexed: 10/26/2022]
Abstract
Nerve injury and inflammation can both induce neuropathic pain via the production of pro-inflammatory cytokines. In the process, G protein-coupled receptors (GPCRs) were involved in pain signal transduction. GPCR kinase (GRK) 6 is a member of the GRK family that regulates agonist-induced desensitization and signaling of GPCRs. However, its expression and function in neuropathic pain have not been reported. In this study, we performed a chronic constriction injury (CCI) model in adult male rats and investigated the dynamic change of GRK6 expression in spinal cord. GRK6 was predominantly expressed in the superficial layers of the lumbar spinal cord dorsal horn neurons and its expression was decreased bilaterally following induction of CCI. The changes of GRK6 were mainly in IB4 and P substrate positive areas in spinal cord dorsal horn. And over-expression of GRK6 in spinal cord by lentivirus intrathecal injection attenuated the pain response induced by CCI. In addition, the level of TNF-α underwent the negative pattern of GRK6 in spinal cord. And neutralized TNF-α by antibody intrathecal injection up-regulated GRK6 expression and attenuated the mechanical allodynia and heat hyperalgesia in CCI model. All the data indicated that down-regulation of neuronal GRK6 expression induced by cytokine may be a potential mechanism that contributes to increasing neuronal signaling in neuropathic pain.
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26
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Ghanemi A. Targeting G protein coupled receptor-related pathways as emerging molecular therapies. Saudi Pharm J 2013; 23:115-29. [PMID: 25972730 PMCID: PMC4420995 DOI: 10.1016/j.jsps.2013.07.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 07/29/2013] [Indexed: 12/20/2022] Open
Abstract
G protein coupled receptors (GPCRs) represent the most important targets in modern pharmacology because of the different functions they mediate, especially within brain and peripheral nervous system, and also because of their functional and stereochemical properties. In this paper, we illustrate, via a variety of examples, novel advances about the GPCR-related molecules that have been shown to play diverse roles in GPCR pathways and in pathophysiological phenomena. We have exemplified how those GPCRs’ pathways are, or might constitute, potential targets for different drugs either to stimulate, modify, regulate or inhibit the cellular mechanisms that are hypothesized to govern some pathologic, physiologic, biologic and cellular or molecular aspects both in vivo and in vitro. Therefore, influencing such pathways will, undoubtedly, lead to different therapeutical applications based on the related pharmacological implications. Furthermore, such new properties can be applied in different fields. In addition to offering fruitful directions for future researches, we hope the reviewed data, together with the elements found within the cited references, will inspire clinicians and researchers devoted to the studies on GPCR’s properties.
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Affiliation(s)
- Abdelaziz Ghanemi
- Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China
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27
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Sternberg Z. Autonomic dysfunction: A unifying multiple sclerosis theory, linking chronic cerebrospinal venous insufficiency, vitamin D3, and Epstein-Barr virus. Autoimmun Rev 2012; 12:250-9. [DOI: 10.1016/j.autrev.2012.04.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Accepted: 04/22/2012] [Indexed: 12/18/2022]
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28
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Cosentino M, Marino F. Adrenergic and dopaminergic modulation of immunity in multiple sclerosis: teaching old drugs new tricks? J Neuroimmune Pharmacol 2012; 8:163-79. [PMID: 23074017 DOI: 10.1007/s11481-012-9410-z] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Accepted: 10/01/2012] [Indexed: 01/11/2023]
Abstract
Multiple sclerosis (MS) is an autoimmune disorder of the CNS characterized by inflammation, demyelination and axonal loss. Classical evidence in experimental allergic encephalomyelitis, the animal model of MS, support the relevance of sympatoadrenergic as well as of dopaminergic mechanisms. In MS patients, dysregulation of adrenergic and dopaminergic pathways contribute to the disease in immune system cells as well as in glial cells. Available evidence is summarized and discussed also in the light of the novel role of dopamine, noradrenaline and adrenaline as transmitters in immune cells, providing a conceptual frame to exploit the potential of several dopaminergic and adrenergic agents, already in clinical use for non-immune indications and with a usually favourable risk-benefit profile, as add-on drugs to conventional immunomodulating therapies in MS.
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Affiliation(s)
- Marco Cosentino
- Center for Research in Medical Pharmacology, University of Insubria, Via Ottorino Rossi n. 9, 21100 Varese, VA, Italy.
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29
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End-point effector stress mediators in neuroimmune interactions: their role in immune system homeostasis and autoimmune pathology. Immunol Res 2012; 52:64-80. [PMID: 22396175 DOI: 10.1007/s12026-012-8275-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Much evidence has identified a direct anatomical and functional link between the brain and the immune system, with glucocorticoids (GCs), catecholamines (CAs), and neuropeptide Y (NPY) as its end-point mediators. This suggests the important role of these mediators in immune system homeostasis and the pathogenesis of inflammatory autoimmune diseases. However, although it is clear that these mediators can modulate lymphocyte maturation and the activity of distinct immune cell types, their putative role in the pathogenesis of autoimmune disease is not yet completely understood. We have contributed to this field by discovering the influence of CAs and GCs on fine-tuning thymocyte negative selection and, in particular, by pointing to the putative CA-mediated mechanisms underlying this influence. Furthermore, we have shown that CAs are implicated in the regulation of regulatory T-cell development in the thymus. Moreover, our investigations related to macrophage biology emphasize the complex interaction between GCs, CAs and NPY in the modulation of macrophage functions and their putative significance for the pathogenesis of autoimmune inflammatory diseases.
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30
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Gurevich EV, Tesmer JJG, Mushegian A, Gurevich VV. G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacol Ther 2012; 133:40-69. [PMID: 21903131 PMCID: PMC3241883 DOI: 10.1016/j.pharmthera.2011.08.001] [Citation(s) in RCA: 336] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Accepted: 08/01/2011] [Indexed: 12/24/2022]
Abstract
G protein-coupled receptor (GPCR) kinases (GRKs) are best known for their role in homologous desensitization of GPCRs. GRKs phosphorylate activated receptors and promote high affinity binding of arrestins, which precludes G protein coupling. GRKs have a multidomain structure, with the kinase domain inserted into a loop of a regulator of G protein signaling homology domain. Unlike many other kinases, GRKs do not need to be phosphorylated in their activation loop to achieve an activated state. Instead, they are directly activated by docking with active GPCRs. In this manner they are able to selectively phosphorylate Ser/Thr residues on only the activated form of the receptor, unlike related kinases such as protein kinase A. GRKs also phosphorylate a variety of non-GPCR substrates and regulate several signaling pathways via direct interactions with other proteins in a phosphorylation-independent manner. Multiple GRK subtypes are present in virtually every animal cell, with the highest expression levels found in neurons, with their extensive and complex signal regulation. Insufficient or excessive GRK activity was implicated in a variety of human disorders, ranging from heart failure to depression to Parkinson's disease. As key regulators of GPCR-dependent and -independent signaling pathways, GRKs are emerging drug targets and promising molecular tools for therapy. Targeted modulation of expression and/or of activity of several GRK isoforms for therapeutic purposes was recently validated in cardiac disorders and Parkinson's disease.
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Affiliation(s)
- Eugenia V Gurevich
- Department of Pharmacology, Vanderbilt University, 2200 Pierce Avenue, Preston Research Building, Rm. 454, Nashville, TN 37232, United States.
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31
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Marino F, Cosentino M. Adrenergic modulation of immune cells: an update. Amino Acids 2011; 45:55-71. [PMID: 22160285 DOI: 10.1007/s00726-011-1186-6] [Citation(s) in RCA: 117] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Accepted: 11/23/2011] [Indexed: 12/25/2022]
Abstract
Sympathoadrenergic pathways are crucial to the communication between the nervous system and the immune system. The present review addresses emerging issues in the adrenergic modulation of immune cells, including: the specific pattern of adrenoceptor expression on immune cells and their role and changes upon cell differentiation and activation; the production and utilization of noradrenaline and adrenaline by immune cells themselves; the dysregulation of adrenergic immune mechanisms in disease and their potential as novel therapeutic targets. A wide array of sympathoadrenergic therapeutics is currently used for non-immune indications, and could represent an attractive source of non-conventional immunomodulating agents.
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Affiliation(s)
- Franca Marino
- Department of Clinical Medicine, Section of Experimental and Clinical Pharmacology, University of Insubria, Via Ottorino Rossi n. 9, 21100 Varese, VA, Italy
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32
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Patial S, Saini Y, Parvataneni S, Appledorn DM, II GWD, LaPres JJ, Amalfitano A, Senagore P, Parameswaran N. Myeloid-specific GPCR kinase-2 negatively regulates NF-κB1p105-ERK pathway and limits endotoxemic shock in mice. J Cell Physiol 2011; 226:627-37. [PMID: 20717897 PMCID: PMC3013243 DOI: 10.1002/jcp.22384] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
G-protein-coupled receptor kinase 2 (GRK2) is a member of a kinase family originally discovered for its role in the phosphorylation and desensitization of G-protein-coupled receptors. It is expressed in high levels in myeloid cells and its levels are altered in many inflammatory disorders including sepsis. To address the physiological role of myeloid cell-specific GRK2 in inflammation, we generated mice bearing GRK2 deletion in myeloid cells (GRK2▵mye). GRK2▵mye mice exhibited exaggerated inflammatory cytokine/chemokine production, and organ injury in response to lipopolysaccharide (LPS, a TLR4 ligand) when compared to wild-type littermates (GRK2fl/fl). Consistent with this, peritoneal macrophages from GRK2▵mye mice showed enhanced inflammatory cytokine levels when stimulated with LPS. Our results further identify TLR4-induced NF-κB1p105-ERK pathway to be selectively regulated by GRK2. LPS-induced activation of NF-κB1p105-MEK-ERK pathway is significantly enhanced in the GRK2▵mye macrophages compared to GRK2fl/fl cells and importantly, inhibition of the p105 and ERK pathways in the GRK2▵mye macrophages, limits the enhanced production of LPS-induced cytokines/chemokines. Taken together, our studies reveal previously undescribed negative regulatory role for GRK2 in TLR4-induced p105-ERK pathway as well as in the consequent inflammatory cytokine/chemokine production and endotoxemia in mice.
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Affiliation(s)
- Sonika Patial
- Department of Physiology and Division of Pathology, Michigan State University, East Lansing, MI
- Program in Cell and Molecular Biology, Michigan State University, East Lansing, MI
| | - Yogesh Saini
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI
| | - Sitaram Parvataneni
- Department of Physiology and Division of Pathology, Michigan State University, East Lansing, MI
| | - Daniel M. Appledorn
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI
| | - Gerald W. Dorn II
- Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - John J. LaPres
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI
| | - Andrea Amalfitano
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI
| | - Patricia Senagore
- Department of Physiology and Division of Pathology, Michigan State University, East Lansing, MI
| | - Narayanan Parameswaran
- Department of Physiology and Division of Pathology, Michigan State University, East Lansing, MI
- Program in Cell and Molecular Biology, Michigan State University, East Lansing, MI
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33
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Kenakin T, Miller LJ. Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol Rev 2010; 62:265-304. [PMID: 20392808 PMCID: PMC2879912 DOI: 10.1124/pr.108.000992] [Citation(s) in RCA: 464] [Impact Index Per Article: 30.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
It is useful to consider seven transmembrane receptors (7TMRs) as disordered proteins able to allosterically respond to a number of binding partners. Considering 7TMRs as allosteric systems, affinity and efficacy can be thought of in terms of energy flow between a modulator, conduit (the receptor protein), and a number of guests. These guests can be other molecules, receptors, membrane-bound proteins, or signaling proteins in the cytosol. These vectorial flows of energy can yield standard canonical guest allostery (allosteric modification of drug effect), effects along the plane of the cell membrane (receptor oligomerization), or effects directed into the cytosol (differential signaling as functional selectivity). This review discusses these apparently diverse pharmacological effects in terms of molecular dynamics and protein ensemble theory, which tends to unify 7TMR behavior toward cells. Special consideration will be given to functional selectivity (biased agonism and biased antagonism) in terms of mechanism of action and potential therapeutic application. The explosion of technology that has enabled observation of diverse 7TMR behavior has also shown how drugs can have multiple (pluridimensional) efficacies and how this can cause paradoxical drug classification and nomenclatures.
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Affiliation(s)
- Terry Kenakin
- GlaxoSmithKline, 5 Moore Drive, Mailtstop V-287, Research Triangle Park, NC 27709, USA.
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34
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Zaffaroni M, Marino F, Bombelli R, Rasini E, Monti M, Ferrari M, Ghezzi A, Comi G, Lecchini S, Cosentino M. Therapy with interferon-beta modulates endogenous catecholamines in lymphocytes of patients with multiple sclerosis. Exp Neurol 2008; 214:315-21. [PMID: 18824168 DOI: 10.1016/j.expneurol.2008.08.015] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Revised: 08/14/2008] [Accepted: 08/29/2008] [Indexed: 01/20/2023]
Abstract
OBJECTIVE To investigate the endogenous dopaminergic/adrenergic system of lymphocytes in multiple sclerosis (MS) patients during treatment with interferon (IFN)-beta. METHODS Patients with relapsing-remitting MS undergoing IFN-beta treatment were prospectively studied during the first year of treatment. Circulating lymphocytes were obtained at baseline and after 1, 3, 6 and 12 months of treatment and assayed for catecholamine (CA) production and mRNA expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in the synthesis of CA), beta(2)-adrenoceptors (AR) and D2, D3 and D5 dopaminergic receptors (DR). RESULTS In cells from patients treated with IFN-beta for 12 months the production of CA hugely increased and was less sensitive to IFN-gamma-induced inhibition. Expression of mRNA for TH, beta(2)-AR and DRD5 was already enhanced after 1 month and further increased up to 6-12 months of treatment. On the contrary, DRD2 mRNA progressively decreased and DRD3 mRNA did not significantly change over the whole study period. CONCLUSIONS In MS patients IFN-beta treatment enhances the ability of lymphocytes to produce CA, and induces extensive modifications of both beta(2)-AR and DR-operated pathways. The clinical relevance of these effects deserves consideration.
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Affiliation(s)
- Mauro Zaffaroni
- Multiple Sclerosis Center, Hospital S. Antonio Abate, Gallarate, VA, Italy
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35
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Golan D, Somer E, Dishon S, Cuzin-Disegni L, Miller A. Impact of exposure to war stress on exacerbations of multiple sclerosis. Ann Neurol 2008; 64:143-8. [DOI: 10.1002/ana.21409] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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36
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Martinez-Forero I, Garcia-Munoz R, Martinez-Pasamar S, Inoges S, Lopez-Diaz de Cerio A, Palacios R, Sepulcre J, Moreno B, Gonzalez Z, Fernandez-Diez B, Melero I, Bendandi M, Villoslada P. IL-10 suppressor activity andex vivo Tr1 cell function are impaired in multiple sclerosis. Eur J Immunol 2008; 38:576-86. [DOI: 10.1002/eji.200737271] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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37
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Sherrill JD, Miller WE. Desensitization of herpesvirus-encoded G protein-coupled receptors. Life Sci 2008; 82:125-34. [PMID: 18054964 PMCID: PMC2239238 DOI: 10.1016/j.lfs.2007.10.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2007] [Revised: 10/15/2007] [Accepted: 10/31/2007] [Indexed: 11/28/2022]
Abstract
Members of the herpesvirus family, including human cytomegalovirus (HCMV) and Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8), encode G protein-coupled receptor (GPCR) homologs, which strongly activate classical G protein signal transduction networks within the cell. In animal models of herpesvirus infection, the viral GPCRs appear to play physiologically important roles by enabling viral replication within tropic tissues and by promoting reactivation from latency. While a number of studies have defined intracellular signaling pathways activated by herpesviral GPCRs, it remains unclear if their physiological function is subjected to the process of desensitization as observed for cellular GPCRs. G protein-coupled receptor kinases (GRK) and arrestin proteins have been recently implicated in regulating viral GPCR signaling; however, the role that these desensitization proteins play in viral GPCR function in vivo remains unknown. Here, we review what is currently known regarding viral GPCR desensitization and discuss potential biological ramifications of viral GPCR regulation by the host cell desensitization machinery.
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Affiliation(s)
- Joseph D Sherrill
- Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, USA
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38
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Abstract
The central nervous system (CNS) and the immune system are two extremely complex and highly adaptive systems. In the face of a real or anticipated threat, be it physical (eg, infection) or psychological (eg, psychosocial stress) in nature, the two systems act in concert to provide optimal adaptation to the demanding internal or environmental conditions. During instances of well being, the communication between these two systems is well tuned and balanced. However, a disturbed crosstalk between the CNS and the immune system is thought to play a major role in a wide series of disorders characterized by a hyporesponsive or hyperresponsive immune system. In multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease, an excess of inflammatory processes seems to be a hallmark and there is growing evidence for a disturbed communication between the CNS and the immune system as a crucial pathogenic factor. While the exact mechanisms for these phenomena are still poorly understood, the young discipline of psychoneuroimmunology (PNI), which focuses on the mechanism underlying the brain to immune crosstalk, might offer some insights into the existing pathogenic mechanisms. Findings from the field of PNI might also help to gain a better understanding regarding the origin and course of MS clinical symptoms such as fatigue and depression.
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Affiliation(s)
- S Kern
- Technische Universität Dresden, Klinik und Poliklinik für Neurologie, Multiple Sklerose Zentrum Dresden, Fetscherstr 74, 01307 Dresden, Germany.
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39
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Calonge M, De Salamanca AE, Siemasko KF, Diebold Y, Gao J, Juárez-Campo M, Stern ME. Variation in the expression of inflammatory markers and neuroreceptors in human conjunctival epithelial cells. Ocul Surf 2007; 3:S145-8. [PMID: 17216105 DOI: 10.1016/s1542-0124(12)70241-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The purpose of this research was to investigate the role of neurogenic involvement in the etiopatho-genesis of ocular surface inflammation, with the final goal of identifying new potential anti-inflammatory agents. We describe the presence of two "classic" markers of inflammation (HLA-DR and ICAM-1) and some neuroreceptors in cultured human conjunctival epithelial cells under basal and pro-inflammatory conditions. Two markers of inflammation (HLA-DR, ICAM-1) and several neuroreceptor subtypes (M1-, M2-, and M3-muscarinic; alpha1A-, alpha1B-, alpha1D-, alpha2A-, alpha2B-, alpha2C-, beta1-, beta2-, and beta3-adrenergic) were analyzed in a normal human conjunctival epithelial cell line (IOBA-NHC). These markers were studied in basal conditions and under the influence of two pro-inflammatory cytokines: tumor necrosis factor alpha (TNF-alpha) and/or interferon gamma (IFN-gamma). Immunofluorescence (confocal microscopy), western blotting, or flow cytometry techniques were used. In basal conditions, epithelial cells expressed all inflammatory markers except HLA-DR. The addition of IFN-gamma enhanced expression of HLA-DR, ICAM-1, and M2-muscarinic receptor. TNF-alpha up-regulated the expression of ICAM-1. When epithelial cells were incubated in the presence of both cytokines together, the cell surface expression of HLA-DR, ICAM-1, alpha1B-, and alpha2B-adrenergic receptors was increased. Cultured human conjunctival epithelial cells have been shown to be susceptible to up-regulation of the expression of inflammatory markers and cell membrane expression of some neuroreceptors under pro-inflammatory conditions. Consequently, pharmacologic neuro-modulation could have a role in the comprehensive management of ocular surface inflammation.
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40
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Heesen C, Mohr DC, Huitinga I, Bergh FT, Gaab J, Otte C, Gold SM. Stress regulation in multiple sclerosis: current issues and concepts. Mult Scler 2007; 13:143-8. [PMID: 17439878 DOI: 10.1177/1352458506070772] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Since its first description by Charcot, psychological stress has been considered a triggering factor for exacerbations in multiple sclerosis, but until recently the clinical evidence for a causal relation was weak. Over the past years, a growing number of studies have started to elucidate this association and highlight potential mechanisms, including brain-immune communication. On 5 June 2005, a panel of international researchers discussed the current evidence. This article summarizes the observational, animal experimental, as well as human experimental findings on stress regulation in MS, as well as studies on the functioning of the major stress response systems, ie, the hypothalamo-pituitary-adrenal (HPA) axis and the autonomous nervous system (ANS) in MS. Consensus statements from the group to these aspects are given. Research objectives and strategies are delineated, as well as clinical implications.
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Affiliation(s)
- C Heesen
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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41
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Wahle M, Hanefeld G, Brunn S, Straub RH, Wagner U, Krause A, Häntzschel H, Baerwald CGO. Failure of catecholamines to shift T-cell cytokine responses toward a Th2 profile in patients with rheumatoid arthritis. Arthritis Res Ther 2007; 8:R138. [PMID: 16889669 PMCID: PMC1779439 DOI: 10.1186/ar2028] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2006] [Revised: 07/11/2006] [Accepted: 08/06/2006] [Indexed: 11/10/2022] Open
Abstract
To further understand the role of neuro-immunological interactions in the pathogenesis of rheumatoid arthritis (RA), we studied the influence of sympathetic neurotransmitters on cytokine production of T cells in patients with RA. T cells were isolated from peripheral blood of RA patients or healthy donors (HDs), and stimulated via CD3 and CD28. Co-incubation was carried out with epinephrine or norepinephrine in concentrations ranging from 10(-5) M to 10(-11) M. Interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-4, and IL-10 were determined in the culture supernatant with enzyme-linked immunosorbent assay. In addition, IFN-gamma and IL-10 were evaluated with intracellular cytokine staining. Furthermore, basal and agonist-induced cAMP levels and catecholamine-induced apoptosis of T cells were measured. Catecholamines inhibited the synthesis of IFN-gamma, TNF-alpha, and IL-10 at a concentration of 10(-5) M. In addition, IFN-gamma release was suppressed by 10(-7) M epinephrine. Lower catecholamine concentrations exerted no significant effect. A reduced IL-4 production upon co-incubation with 10(-5) M epinephrine was observed in RA patients only. The inhibitory effect of catecholamines on IFN-gamma production was lower in RA patients as compared with HDs. In RA patients, a catecholamine-induced shift toward a Th2 (type 2) polarised cytokine profile was abrogated. Evaluation of intracellular cytokines revealed that CD8-positive T cells were accountable for the impaired catecholaminergic control of IFN-gamma production. The highly significant negative correlation between age and catecholamine effects in HDs was not found in RA patients. Basal and stimulated cAMP levels in T-cell subsets and catecholamine-induced apoptosis did not differ between RA patients and HDs. RA patients demonstrate an impaired inhibitory effect of catecholamines on IFN-gamma production together with a failure to induce a shift of T-cell cytokine responses toward a Th2-like profile. Such an unfavorable situation is a perpetuating factor for inflammation.
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Affiliation(s)
- Matthias Wahle
- Department of Internal Medicine IV, University Hospital Leipzig, Liebigstrasse 22, 04103 Leipzig, Germany
| | - Gesine Hanefeld
- Department of Internal Medicine IV, University Hospital Leipzig, Liebigstrasse 22, 04103 Leipzig, Germany
| | - Stephan Brunn
- Department of Internal Medicine IV, University Hospital Leipzig, Liebigstrasse 22, 04103 Leipzig, Germany
| | - Rainer H Straub
- Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany
| | - Ulf Wagner
- Department of Internal Medicine IV, University Hospital Leipzig, Liebigstrasse 22, 04103 Leipzig, Germany
| | - Andreas Krause
- Immanuel Hospital, Rheumatology Clinic, Königstrasse 63, 14109 Berlin, Germany
| | - Holm Häntzschel
- Department of Internal Medicine IV, University Hospital Leipzig, Liebigstrasse 22, 04103 Leipzig, Germany
| | - Christoph GO Baerwald
- Department of Internal Medicine IV, University Hospital Leipzig, Liebigstrasse 22, 04103 Leipzig, Germany
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42
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Heijnen CJ. Receptor regulation in neuroendocrine-immune communication: current knowledge and future perspectives. Brain Behav Immun 2007; 21:1-8. [PMID: 17029700 DOI: 10.1016/j.bbi.2006.08.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2006] [Revised: 08/10/2006] [Accepted: 08/12/2006] [Indexed: 11/19/2022] Open
Abstract
Immune cells express receptors for every hormone or neurotransmitter we know so far. The neuroendocrine system signals to the immune system via the release of hormones and neurotransmitters that regulate cellular activity via these receptors. Much attention has been focused on the effect of glucocorticoids and catecholamines on the immune system. Glucocorticoids communicate with immune cells via glucocorticoid receptors of which the activity itself changes during immune activation. Many neuroendocrine mediators are ligands for G-protein coupled receptors on immune cells. Cytokines, oxygen-radicals, and catecholamines can influence the responsiveness of G-protein coupled receptors via decreasing the intracellular level of so-called G-protein coupled receptor kinases, of which the subtype GRK2 is highly expressed in immune cells. Therefore, changes in only one kinase can modulate the sensitivity of many receptors. We describe here that sensitivity of neuroendocrine receptors on immune cells is constantly regulated by inflammatory processes or chronic stress, which implies that not only the activity of the neuroendocrine system determines communication but that the sensitivity of receptors is a major factor in determining the final immune response. Finally, consequences of alterations in GRK2 during (neuro)-inflammatory diseases are discussed.
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Affiliation(s)
- Cobi J Heijnen
- Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
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43
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Abstract
G-protein-coupled receptor kinases (GRKs) interact with the agonist-activated form of G-protein-coupled receptor (GPCR) to affect receptor phosphorylation and to initiate profound impairment of receptor signaling, or desensitization. GPCR forms the largest family of cell surface receptors, and defects in GRK function have the potential consequence to affect GPCR-stimulated biological responses in many pathological situations.
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Affiliation(s)
- Wen Yang
- Department of Gastroenterology, Pancreas Center, Affiliated Hospital of Medical College of the Chinese People's Armed Police Forces, Chenglinzhuang Road, Tianjin 300162, China
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44
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Schulz KH, Gold S. [Psychological stress, immune function and disease development. The psychoneuroimmunologic perspective]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2006; 49:759-72. [PMID: 16865632 DOI: 10.1007/s00103-006-0006-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Interdisciplinary psychoneuroimmunological (PNI) research increasingly demonstrates clinically relevant interrelations between psychological stressors and the onset or progression of chronic diseases. Disturbances of the bi-directional interaction between the nervous system, the immune system and the endocrine system have been hypothesized to be implicated in several diseases. Here, we review evidence from psychoneuroimmunology within the theoretical framework of allostatic load to conceptualize some of these associations. Interdisciplinary PNI research investigating the importance of psychological stress for the higher incidence of infections, decreased responses to vaccinations and delayed wound healing is reviewed. Furthermore, the literature supporting similar associations with regard to progression of oncological diseases and autoimmune disorders is reviewed with a focus on breast cancer and multiple sclerosis. The accumulating evidence regarding the importance of neuroendocrine-immune interaction in these diseases may thus lead to novel insights into pathogenetic mechanisms and could contribute to the development of novel preventive and therapeutic strategies.
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Affiliation(s)
- K-H Schulz
- Universitätsklinikum Eppendorf, Transplantationszentrum und Institut für Medizinische Psychologie, Martinistrasse 52, Gebäude S35, 20246 Hamburg, BRD.
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45
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Vroon A, Heijnen CJ, Kavelaars A. GRKs and arrestins: regulators of migration and inflammation. J Leukoc Biol 2006; 80:1214-21. [PMID: 16943386 DOI: 10.1189/jlb.0606373] [Citation(s) in RCA: 125] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
In the immune system, signaling by G protein-coupled receptors (GPCRs) is crucial for the activity of multiple mediators, including chemokines, leukotrienes, and neurotransmitters. GPCR kinases (GRKs) and arrestins control GPCR signaling by mediating desensitization and thus, regulating further signal propagation through G proteins. Recent evidence suggests that the GRK-arrestin desensitization machinery fulfills a vital role in regulating inflammatory processes. First, GRK/arrestin levels in immune cells are dynamically regulated in response to inflammation. Second, in animals with targeted deletion of GRKs or arrestins, the progression of various acute and chronic inflammatory disorders, including autoimmunity and allergy, is profoundly affected. Third, chemokine receptor signaling in vitro is known to be tightly regulated by the GRK/arrestin machinery, and even small changes in GRK/arrestin expression can have a marked effect on cellular responses to chemokines. This review integrates data about the role of GRKs and arrestins in inflammation, with results on the molecular mechanism of action of GRKs/arrestins, and describes the pivotal role of GRKs/arrestins in inflammatory processes, with a special emphasis on regulation of chemokine responsiveness.
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Affiliation(s)
- Anne Vroon
- Department of Psychoneuroimmunology, Room KC03.063.0, Lundlaan 6, 3584 EA, Utrecht, The Netherlands
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46
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Sanders VM. Adrenergic receptors on T and B lymphocytes: Evidence, function, and clinical implications. ACTA ACUST UNITED AC 2006. [DOI: 10.1016/j.cnr.2006.05.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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47
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Gold SM, Heesen C. Stress and disease progression in multiple sclerosis and its animal models. Neuroimmunomodulation 2006; 13:318-26. [PMID: 17709954 DOI: 10.1159/000104860] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Since the first description of multiple sclerosis (MS) by Charcot, stress has been hypothesized to be a potential trigger of relapses. In recent years, data from observational studies in MS patients have provided some support for an association between stress and MS relapses. Furthermore, studies employing the MS animal model experimental autoimmune encephalomyelitis have shown that certain stressors can exacerbate the disease if administered prior to disease induction. Several lines of research have explored the 2 major stress response systems--the hypothalamic-pituitary-adrenal axis and the autonomic nervous system--and their relation to disease course in MS and experimental autoimmune encephalomyelitis. These studies provide evidence that insensitivity of the immune system to signals from these systems may play a role in inflammatory events. These findings can be integrated into a biological model of stress response system alterations in MS.
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Affiliation(s)
- Stefan M Gold
- Multiple Sclerosis Program, Department of Neurology and Cousins Center for Psychoneuroimmunology, UCLA School of Medicine, Los Angeles, CA 90095, USA, and University Hospital Hamburg-Eppendorf, Germany.
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48
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Gold SM, Mohr DC, Huitinga I, Flachenecker P, Sternberg EM, Heesen C. The role of stress-response systems for the pathogenesis and progression of MS. Trends Immunol 2005; 26:644-52. [PMID: 16214415 DOI: 10.1016/j.it.2005.09.010] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2005] [Revised: 09/02/2005] [Accepted: 09/22/2005] [Indexed: 11/19/2022]
Abstract
Disease progression in multiple sclerosis (MS)--an inflammatory demyelinating and neurodegenerative disease with a presumed T-cell driven autoimmune origin--has long been hypothesized to be associated with stress. However, this notion has only recently been supported by prospective clinical studies. Several clinical and molecular studies in MS and its animal models have recently shown disruptions in the communication between the immune system and the two major stress response systems, the hypothalamo-pituitary-adrenal (HPA) axis and the autonomic nervous system. Insensitivity to glucocorticoid and beta-adrenergic modulation might be involved in overshooting inflammation in MS, whereas hyperactivity of the HPA axis has been linked to neurodegeneration and increased disability. Here, we integrate findings from molecular, cellular, experimental, clinical and epidemiological research to describe the involvement of stress response systems in MS pathogenesis and progression.
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Affiliation(s)
- Stefan M Gold
- Multiple Sclerosis Program, Department of Neurology and Cousins Center for Psychoneuroimmunology, Neuropsychiatric Institute, UCLA School of Medicine, NRB1 (Rm 479), 635 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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49
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Giorelli M, Livrea P, Trojano M. Dopamine fails to regulate activation of peripheral blood lymphocytes from multiple sclerosis patients: effects of IFN-beta. J Interferon Cytokine Res 2005; 25:395-406. [PMID: 16022584 DOI: 10.1089/jir.2005.25.395] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The neurotransmitter dopamine counteracts T cell functions through its specific receptor subtype D5R but favors T cell proliferation and adhesion when acting on D3R. We found diminished mRNA and protein levels of D5R, but not of D3R, in peripheral blood mononuclear cells (PBMCs) from untreated multiple sclerosis (MS) patients. Dopamine reduced T cell proliferation, secretion of interferon-gamma (IFN-gamma), and production of matrix metalloproteinase-9 (MMP-9) mRNA in PBMCs from controls but not from MS patients. By contrast, reduced levels of D3R and renewed dopamine-associated regulatory functions were found in PBMCs from IFN-beta treated MS patients. Failure of the dopaminergic system of lymphocytes may lessen the threshold of T cell activation and sustain the pathogenic cascade of MS.
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Affiliation(s)
- Maurizio Giorelli
- Department of Neurologic and Psychiatric Sciences, University of Bari, Bari, Italy.
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50
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Cosentino M, Zaffaroni M, Ferrari M, Marino F, Bombelli R, Rasini E, Frigo G, Ghezzi A, Comi G, Lecchini S. Interferon-gamma and interferon-beta affect endogenous catecholamines in human peripheral blood mononuclear cells: implications for multiple sclerosis. J Neuroimmunol 2005; 162:112-21. [PMID: 15833366 DOI: 10.1016/j.jneuroim.2005.01.019] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2004] [Revised: 01/25/2005] [Accepted: 01/26/2005] [Indexed: 02/05/2023]
Abstract
Interferon (IFN)-gamma plays a pivotal role in the pathogenesis of multiple sclerosis (MS), while IFN-beta may be able to modify the clinical course of the disease, eventually also by counterbalancing IFN-gamma-mediated effects. Catecholamines (CA) exert important effects on the immune response, both as transmitters between the nervous and the immune system, as well as autocrine/paracrine mediators in immune cells, and several lines of evidence support their involvement in MS. In particular, dysregulated production of CA seems to occur in peripheral blood mononuclear cells (PBMCs) of MS patients. We assessed the effects of IFN-beta and IFN-gamma on endogenous CA in PBMCs. In cultured PBMCs stimulated with phytohaemagglutinin (PHA), IFN-beta increased CA production and induced CA release in the culture medium, while IFN-gamma decreased both CA production and the expression of mRNA for the CA-synthesizing enzyme tyrosine hydroxylase. Coincubation with both IFNs prevented the inhibitory effect of IFN-gamma, as well as the stimulatory effect of IFN-beta. IFNs are the first physiological compounds shown to affect endogenous CA in PBMCs: in view of the role of CA-dependent mechanisms in the immune response, these findings may help to better understand the mechanisms of action of IFN-beta as an immunomodulatory drug in MS.
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Affiliation(s)
- Marco Cosentino
- Department of Clinical Medicine, Section of Experimental and Clinical Pharmacology, University of Insubria, Via Ottorino Rossi n. 9, 21100 Varese VA, Italy.
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