Thomas Hach, Kasra Shakeri-Nejad, Marc Bigaud, Frank Dahlke, Massimiliano de Micco, Olivier Petricoul, Gordon Graham, Daniela Piani-Meier, Renato Turrini, Volker Brinkmann, Ferdinando Nicoletti
Maladjusted immune responses to the coronavirus disease 2019 (COVID-19), for example, cytokine release syndrome, may result in immunopathology and acute respiratory distress syndrome. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, and its S1P receptor (S1PR) are crucial in maintaining endothelial cell chemotaxis and barrier integrity. Apart from the S1P1 receptor-mediated mechanisms of sequestration of cytotoxic lymphocytes, including Th-17 and S1P1/2/3-mediated endothelial barrier functions, S1PR modulators may also attenuate cytokine release via activation of serine/threonine protein phosphatase 2A and enhance the pulmonary endothelial barrier via the c-Abl tyrosine kinase pathway. Chronic treatment with fingolimod (S1PR1,3,4,5 modulator) and siponimod (S1PR1,5 modulator) has demonstrated efficacy in reducing inflammatory disease activity and slowing down disease progression in multiple sclerosis. The decision to selectively suppress the immunity of a critically ill patient with COVID-19 remains a difficult choice. It has been suggested that treatment with fingolimod or siponimod may be appropriate to attenuate severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced hyperinflammation in patients with COVID-19 since these patients are already monitored in an intensive care setting. Here, we review the use of S1PR modulators, fingolimod and siponimod, in regulating the inflammatory response to SARS-CoV-2 with the aim of understanding their potential rationale use in patients with COVID-19.
{"title":"Rationale for Use of Sphingosine-1-Phosphate Receptor Modulators in COVID-19 Patients: Overview of Scientific Evidence.","authors":"Thomas Hach, Kasra Shakeri-Nejad, Marc Bigaud, Frank Dahlke, Massimiliano de Micco, Olivier Petricoul, Gordon Graham, Daniela Piani-Meier, Renato Turrini, Volker Brinkmann, Ferdinando Nicoletti","doi":"10.1089/jir.2022.0078","DOIUrl":"https://doi.org/10.1089/jir.2022.0078","url":null,"abstract":"<p><p>Maladjusted immune responses to the coronavirus disease 2019 (COVID-19), for example, cytokine release syndrome, may result in immunopathology and acute respiratory distress syndrome. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, and its S1P receptor (S1PR) are crucial in maintaining endothelial cell chemotaxis and barrier integrity. Apart from the S1P1 receptor-mediated mechanisms of sequestration of cytotoxic lymphocytes, including Th-17 and S1P1/2/3-mediated endothelial barrier functions, S1PR modulators may also attenuate cytokine release via activation of serine/threonine protein phosphatase 2A and enhance the pulmonary endothelial barrier via the c-Abl tyrosine kinase pathway. Chronic treatment with fingolimod (S1PR1,3,4,5 modulator) and siponimod (S1PR1,5 modulator) has demonstrated efficacy in reducing inflammatory disease activity and slowing down disease progression in multiple sclerosis. The decision to selectively suppress the immunity of a critically ill patient with COVID-19 remains a difficult choice. It has been suggested that treatment with fingolimod or siponimod may be appropriate to attenuate severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced hyperinflammation in patients with COVID-19 since these patients are already monitored in an intensive care setting. Here, we review the use of S1PR modulators, fingolimod and siponimod, in regulating the inflammatory response to SARS-CoV-2 with the aim of understanding their potential rationale use in patients with COVID-19.</p>","PeriodicalId":16261,"journal":{"name":"Journal of Interferon and Cytokine Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/03/42/jir.2022.0078.PMC10282791.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9703580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mycobacterium tuberculosis (Mtb) infection elicits macrophage polarization into M2 phenotype to block the host's protective immune response. However, it remains unclear how Mtb regulates macrophage polarization. Recent studies have suggested that noncoding RNA may play a role in macrophage polarization. In this study, we investigated the potential involvement of circTRAPPC6B, a circular RNA that is downregulated in tuberculosis (TB) patients, in regulating macrophage polarization. We found that Mtb infection downregulated M1-related IL-6 and IL-1β while highly expressed M2-related CCL22 and CD163. Overexpressed circTRAPPC6B had switched Mtb-infected macrophages from M2- to M1-like phenotype, accompanied by upregulation of IL-6 and IL-1β. Meanwhile overexpressed circTRAPPC6B significantly inhibited Mtb growth in macrophages. Our findings suggest that circTRAPPC6B may regulate macrophage polarization by targeting miR-892c-3p, which is highly expressed in TB patients and M2-like macrophages. And miR-892c-3p inhibitor decreased intracellular Mtb growth in macrophages. Thus, TB-inhibited circTRAPPC6B could specifically induce IL-6 and IL-1β expression to switch/antagonize Mtb-induced macrophage polarization from M2- to M1-like phenotype by targeting miR-892c-3p, leading to enhanced host clearance of Mtb. Our results reveal a potential role for circTRAPPC6B in regulating macrophage polarization during Mtb infection and provide new insights into the molecular mechanisms underlying host defense against Mtb.
{"title":"Circular RNA circTRAPPC6B Enhances IL-6 and IL-1β Expression and Repolarizes <i>Mycobacteria</i> Induced Macrophages from M2- to M1-Like Phenotype by Targeting miR-892c-3p.","authors":"Ying Peng, Xian-Jin Wu, Xue-Jiao Ji, Gui-Xian Huang, Tian Wu, Xi Liu, Rui Yang, Jiang Pi, Hong-Bo Shen, Fei-Fei Wang, Jun-Fa Xu","doi":"10.1089/jir.2023.0007","DOIUrl":"10.1089/jir.2023.0007","url":null,"abstract":"<p><p><i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) infection elicits macrophage polarization into M2 phenotype to block the host's protective immune response. However, it remains unclear how <i>Mtb</i> regulates macrophage polarization. Recent studies have suggested that noncoding RNA may play a role in macrophage polarization. In this study, we investigated the potential involvement of circTRAPPC6B, a circular RNA that is downregulated in tuberculosis (TB) patients, in regulating macrophage polarization. We found that <i>Mtb</i> infection downregulated M1-related IL-6 and IL-1β while highly expressed M2-related CCL22 and CD163. Overexpressed circTRAPPC6B had switched <i>Mtb</i>-infected macrophages from M2- to M1-like phenotype, accompanied by upregulation of IL-6 and IL-1β. Meanwhile overexpressed circTRAPPC6B significantly inhibited <i>Mtb</i> growth in macrophages. Our findings suggest that circTRAPPC6B may regulate macrophage polarization by targeting miR-892c-3p, which is highly expressed in TB patients and M2-like macrophages. And miR-892c-3p inhibitor decreased intracellular <i>Mtb</i> growth in macrophages. Thus, TB-inhibited circTRAPPC6B could specifically induce IL-6 and IL-1β expression to switch/antagonize <i>Mtb</i>-induced macrophage polarization from M2- to M1-like phenotype by targeting miR-892c-3p, leading to enhanced host clearance of <i>Mtb</i>. Our results reveal a potential role for circTRAPPC6B in regulating macrophage polarization during <i>Mtb</i> infection and provide new insights into the molecular mechanisms underlying host defense against <i>Mtb</i>.</p>","PeriodicalId":16261,"journal":{"name":"Journal of Interferon and Cytokine Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9707913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sara Bolívar-Marín, Marcela Castro, Diego Losada-Floriano, Santiago Cortés, Federico Perdomo-Celis, Giovani Lastra, Carlos F Narváez
Increased systemic levels of inflammatory cytokines have been associated with the development of pathophysiologic events during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To further explore differences in the pattern and dynamics of plasma cytokines in individuals with coronavirus disease-19 (COVID-19), and the relationship with disease mortality, here we evaluated the plasma levels of proinflammatory and regulatory cytokines in Colombian patient survivors and nonsurvivors of SARS-CoV-2 infection. Individuals with confirmed COVID-19, with other respiratory diseases requiring hospitalization, and healthy controls, were included. Plasma levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon-γ, IL-10, soluble tumor necrosis factor receptor I (sTNFRI), and transforming growth factor-β1 were measured by a bead-based assay or enzyme-linked immunosorbent assay and clinical, laboratory, and tomographic parameters were registered during hospitalization. The levels of most of the evaluated cytokines were increased in COVID-19 individuals relative to healthy controls. The levels of IL-6, IL-10, and sTNFRI were directly associated with the development of respiratory failure, immune dysregulation, and coagulopathy, as well as with COVID-19 mortality. Particularly, the early, robust, and persistent increase of circulating IL-6 characterized COVID-19 nonsurvivors, while survivors were able to counteract the inflammatory cytokine response. In addition, IL-6 systemic levels positively correlated with the tomographic extension of lung damage in individuals with COVID-19. Thus, an exacerbated inflammatory cytokine response, particularly mediated by IL-6 added to the inefficiency of regulatory cytokines, distinguishes COVID-19-associated tissue disturbances, severity, and mortality in Colombian adults.
{"title":"A Specific Pattern and Dynamics of Circulating Cytokines Are Associated with the Extension of Lung Injury and Mortality in Colombian Adults with Coronavirus Disease-19.","authors":"Sara Bolívar-Marín, Marcela Castro, Diego Losada-Floriano, Santiago Cortés, Federico Perdomo-Celis, Giovani Lastra, Carlos F Narváez","doi":"10.1089/jir.2023.0001","DOIUrl":"https://doi.org/10.1089/jir.2023.0001","url":null,"abstract":"<p><p>Increased systemic levels of inflammatory cytokines have been associated with the development of pathophysiologic events during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To further explore differences in the pattern and dynamics of plasma cytokines in individuals with coronavirus disease-19 (COVID-19), and the relationship with disease mortality, here we evaluated the plasma levels of proinflammatory and regulatory cytokines in Colombian patient survivors and nonsurvivors of SARS-CoV-2 infection. Individuals with confirmed COVID-19, with other respiratory diseases requiring hospitalization, and healthy controls, were included. Plasma levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon-γ, IL-10, soluble tumor necrosis factor receptor I (sTNFRI), and transforming growth factor-β1 were measured by a bead-based assay or enzyme-linked immunosorbent assay and clinical, laboratory, and tomographic parameters were registered during hospitalization. The levels of most of the evaluated cytokines were increased in COVID-19 individuals relative to healthy controls. The levels of IL-6, IL-10, and sTNFRI were directly associated with the development of respiratory failure, immune dysregulation, and coagulopathy, as well as with COVID-19 mortality. Particularly, the early, robust, and persistent increase of circulating IL-6 characterized COVID-19 nonsurvivors, while survivors were able to counteract the inflammatory cytokine response. In addition, IL-6 systemic levels positively correlated with the tomographic extension of lung damage in individuals with COVID-19. Thus, an exacerbated inflammatory cytokine response, particularly mediated by IL-6 added to the inefficiency of regulatory cytokines, distinguishes COVID-19-associated tissue disturbances, severity, and mortality in Colombian adults.</p>","PeriodicalId":16261,"journal":{"name":"Journal of Interferon and Cytokine Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9967057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cytokine imbalance is an important feature in the occurrence and outcome of hepatitis B virus (HBV). Single nucleotide polymorphisms (SNPs) within cytokine genes may affect the protein expression and eventually contribute to the susceptibility of HBV infection. The association between interleukin (IL)-12, IL-17, or IL-21 and the risk of HBV infection has been extensively studied, but yielding equivocal results. The aim of this meta-analysis was to determine the impact of SNPs in IL-12, IL-17, and IL-21 on the risk of HBV infection. We retrieved studies evaluating whether SNPs in IL-12, IL-17, and IL-21 influenced HBV infection from electronic databases, including PUBMED, Web of Science, EBOCO, OVID, and Embase. Summarized odds ratios (ORs) and confidence intervals (CIs) were calculated using STATA software. Under a homozygous comparison, the IL-12A rs568408 was associated with an increased risk of HBV infection in both overall analysis (OR = 1.68, 95% CI, 1.12-2.53) and Caucasians (OR = 1.80, 95% CI, 1.14-2.84). Under a dominant genetic model, the similarly higher risk was also observed in overall analysis (OR = 3.62, 95% CI, 3.08-4.24), Caucasians (OR = 3.29, 95% CI, 2.67-4.05), high-quality studies (OR = 3.29, 95% CI, 2.61-4.14), and low-quality studies (OR = 3.95, 95% CI, 3.17-4.93). Although no significant association was observed between IL-17A rs2275913 and the risk of HBV infection in overall comparison, subgroup analysis revealed that the IL-17A rs2275913 AA genotype was associated with a reduced risk in Asians (OR = 0.72, 95% CI, 0.57-0.91) and high-quality studies (OR = 0.71, 95% CI, 0.55-0.92). However, no significant association of IL12B rs3212227, IL-17A rs2275913, IL-21 rs2221903, and rs907715 with HBV infection was observed. In conclusion, we provide evidence that IL-12A rs568408 was associated with an increased risk of HBV infection and IL-17A rs2275913 AA genotype was a protective factor against HBV infection in Asians.
{"title":"A Meta-Analysis of the Association Between Genetic Polymorphisms in <i>IL-12</i>, <i>IL-17</i>, and <i>IL-21</i> and Risk of Hepatitis B Virus Infection.","authors":"Juan Wan, Li Tang, Hongyu Li, Ping Yang","doi":"10.1089/jir.2022.0249","DOIUrl":"https://doi.org/10.1089/jir.2022.0249","url":null,"abstract":"<p><p>Cytokine imbalance is an important feature in the occurrence and outcome of hepatitis B virus (HBV). Single nucleotide polymorphisms (SNPs) within cytokine genes may affect the protein expression and eventually contribute to the susceptibility of HBV infection. The association between interleukin (<i>IL</i>)<i>-12</i>, <i>IL-17</i>, or <i>IL-21</i> and the risk of HBV infection has been extensively studied, but yielding equivocal results. The aim of this meta-analysis was to determine the impact of SNPs in <i>IL-12</i>, <i>IL-17</i>, and <i>IL-21</i> on the risk of HBV infection. We retrieved studies evaluating whether SNPs in <i>IL-12</i>, <i>IL-17</i>, and <i>IL-21</i> influenced HBV infection from electronic databases, including PUBMED, Web of Science, EBOCO, OVID, and Embase. Summarized odds ratios (ORs) and confidence intervals (CIs) were calculated using STATA software. Under a homozygous comparison, the <i>IL-12A</i> rs568408 was associated with an increased risk of HBV infection in both overall analysis (OR = 1.68, 95% CI, 1.12-2.53) and Caucasians (OR = 1.80, 95% CI, 1.14-2.84). Under a dominant genetic model, the similarly higher risk was also observed in overall analysis (OR = 3.62, 95% CI, 3.08-4.24), Caucasians (OR = 3.29, 95% CI, 2.67-4.05), high-quality studies (OR = 3.29, 95% CI, 2.61-4.14), and low-quality studies (OR = 3.95, 95% CI, 3.17-4.93). Although no significant association was observed between <i>IL-17A</i> rs2275913 and the risk of HBV infection in overall comparison, subgroup analysis revealed that the <i>IL-17A</i> rs2275913 AA genotype was associated with a reduced risk in Asians (OR = 0.72, 95% CI, 0.57-0.91) and high-quality studies (OR = 0.71, 95% CI, 0.55-0.92). However, no significant association of <i>IL12B</i> rs3212227, <i>IL-17A</i> rs2275913, <i>IL-21</i> rs2221903, and rs907715 with HBV infection was observed. In conclusion, we provide evidence that <i>IL-12A</i> rs568408 was associated with an increased risk of HBV infection and <i>IL-17A</i> rs2275913 AA genotype was a protective factor against HBV infection in Asians.</p>","PeriodicalId":16261,"journal":{"name":"Journal of Interferon and Cytokine Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10057954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yunfei Zhang, Qianyang Liu, Kai Gao, Bing Tian, Hai Zhu, Jian Liu, Yuhui Hu, Cuilian Ye, Chunbao Guo
In neonates, necrotizing enterocolitis (NEC) is a serious condition involving oxidative stress and inflammation. Remote ischemic conditioning (RIC) is a potentially useful technique to protect distant organs from the damage induced by ischemia. RIC has been verified as effective to protect against NEC; however, its mechanism is unclear. This study aimed to assess the mechanism and efficacy of RIC to treat experimental NEC in mice. Between postnatal day (P) 5 and P9, we induced NEC in C57BL/6 mice and Grx1-/- mice. Intermittent occlusion of the blood flow to the right hind limb for 4 cycles of 5 min ischemia followed by 5 min reperfusion during NEC induction on P6 and P8 was used to apply RIC. We sacrificed the mice on p9 and evaluated oxidative stress, inflammatory cytokines, proliferation, apoptosis, and PI3K/Akt/mTOR signal pathway in mice ileal tissue. RIC decreased intestinal injury and prolonged survival in NEC pups. RIC significantly inhibited inflammatory, attenuated oxidative stress, reduced apoptosis, promoted proliferation, and activated PI3K/Akt/mTOR in vivo. RIC activates the PI3K/Akt/mTOR signaling pathway to control oxidative stress and inflammation. RIC might provide a new therapeutic strategy for NEC.
{"title":"Remote Ischemic Conditioning Relieves Necrotizing Enterocolitis Through Regulation of Redox and Inflammation.","authors":"Yunfei Zhang, Qianyang Liu, Kai Gao, Bing Tian, Hai Zhu, Jian Liu, Yuhui Hu, Cuilian Ye, Chunbao Guo","doi":"10.1089/jir.2023.0015","DOIUrl":"https://doi.org/10.1089/jir.2023.0015","url":null,"abstract":"<p><p>In neonates, necrotizing enterocolitis (NEC) is a serious condition involving oxidative stress and inflammation. Remote ischemic conditioning (RIC) is a potentially useful technique to protect distant organs from the damage induced by ischemia. RIC has been verified as effective to protect against NEC; however, its mechanism is unclear. This study aimed to assess the mechanism and efficacy of RIC to treat experimental NEC in mice. Between postnatal day (P) 5 and P9, we induced NEC in C57BL/6 mice and <i>Grx1</i><sup>-/-</sup> mice. Intermittent occlusion of the blood flow to the right hind limb for 4 cycles of 5 min ischemia followed by 5 min reperfusion during NEC induction on P6 and P8 was used to apply RIC. We sacrificed the mice on p9 and evaluated oxidative stress, inflammatory cytokines, proliferation, apoptosis, and PI3K/Akt/mTOR signal pathway in mice ileal tissue. RIC decreased intestinal injury and prolonged survival in NEC pups. RIC significantly inhibited inflammatory, attenuated oxidative stress, reduced apoptosis, promoted proliferation, and activated PI3K/Akt/mTOR <i>in vivo</i>. RIC activates the PI3K/Akt/mTOR signaling pathway to control oxidative stress and inflammation. RIC might provide a new therapeutic strategy for NEC.</p>","PeriodicalId":16261,"journal":{"name":"Journal of Interferon and Cytokine Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9683485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-01Epub Date: 2023-04-21DOI: 10.1089/jir.2023.0016
Ganes C Sen, Patricia M Kessler
Many pattern recognition receptors in mammalian cells initiate signaling processes that culminate in mounting an innate protective response mediated by induced synthesis of a large number of proteins including type I interferons and other cytokines. Many of these receptors are not located on the plasma membrane but on the membranes of intracellular organelles such as endosomes, mitochondria, and the endoplasmic reticulum; they primarily recognize microbial or cellular nucleic acids. In the course of biochemical analyses of the signaling pathways triggered by these receptors, we discovered that they require tyrosine phosphorylation by the protein kinase activity of the epidermal growth factor receptor (EGFR), which is located not only on the plasma membrane but also on the intracellular membranes. Here, we discuss how specific members of this family of receptors, such as TLR3, TLR9, or STING, interact with EGFR and other protein tyrosine kinases and what are the functional consequences of their post-translational modifications. The article highlights an unexpected functional link between a growth factor receptor and cellular innate immune response.
哺乳动物细胞中的许多模式识别受体启动了信号传导过程,最终通过诱导合成大量蛋白质(包括 I 型干扰素和其他细胞因子)来启动先天性保护反应。其中许多受体并不位于质膜上,而是位于细胞内细胞器(如内体、线粒体和内质网)的膜上;它们主要识别微生物或细胞核酸。在对这些受体触发的信号通路进行生化分析的过程中,我们发现它们需要表皮生长因子受体(EGFR)的蛋白激酶活性进行酪氨酸磷酸化,而表皮生长因子受体不仅位于质膜上,也位于细胞内膜上。在此,我们将讨论该受体家族的特定成员,如 TLR3、TLR9 或 STING,如何与表皮生长因子受体和其他蛋白酪氨酸激酶相互作用,以及它们的翻译后修饰会产生哪些功能性后果。文章强调了生长因子受体与细胞先天性免疫反应之间意想不到的功能联系。
{"title":"Unexpected Need of the Epidermal Growth Factor Receptor Tyrosine Kinase Activity for Signaling by Intracellular Pattern Recognition Receptors of Nucleic Acids.","authors":"Ganes C Sen, Patricia M Kessler","doi":"10.1089/jir.2023.0016","DOIUrl":"10.1089/jir.2023.0016","url":null,"abstract":"<p><p>Many pattern recognition receptors in mammalian cells initiate signaling processes that culminate in mounting an innate protective response mediated by induced synthesis of a large number of proteins including type I interferons and other cytokines. Many of these receptors are not located on the plasma membrane but on the membranes of intracellular organelles such as endosomes, mitochondria, and the endoplasmic reticulum; they primarily recognize microbial or cellular nucleic acids. In the course of biochemical analyses of the signaling pathways triggered by these receptors, we discovered that they require tyrosine phosphorylation by the protein kinase activity of the epidermal growth factor receptor (EGFR), which is located not only on the plasma membrane but also on the intracellular membranes. Here, we discuss how specific members of this family of receptors, such as TLR3, TLR9, or STING, interact with EGFR and other protein tyrosine kinases and what are the functional consequences of their post-translational modifications. The article highlights an unexpected functional link between a growth factor receptor and cellular innate immune response.</p>","PeriodicalId":16261,"journal":{"name":"Journal of Interferon and Cytokine Research","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10210212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9683475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Several inflammatory diseases are characterized by elevated T cell counts and high pro-inflammatory cytokine levels. Inhibiting T cell activity may reduce tissue damage associated with these diseases. Acthar® Gel has potent anti-inflammatory properties, yet little is known about its effect on T cells. This study compared the effects of Acthar, synthetic adrenocorticotropic hormone 1-24 (ACTH1-24) depot, and prednisolone in a murine model of T cell activation. Assessments of CD4+ helper and CD8+ cytotoxic T cells and plasma concentrations of interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α) were made following anti-CD3-activation. Acthar significantly reduced the number of activated CD4+ and CD8+ T cells at amounts comparable to synthetic ACTH1-24 depot or prednisolone. However, Acthar reduced production of IFN-γ, IL-2, and TNF-α significantly more than the other drugs, suggesting that the in vivo immunomodulatory effects of Acthar on T cells are distinct from synthetic ACTH1-24 depot or prednisolone.
{"title":"Acthar Gel Inhibits the Activation of CD4<sup>+</sup> and CD8<sup>+</sup> T Cells.","authors":"Dale Wright, Kyle Hayes","doi":"10.1089/jir.2022.0257","DOIUrl":"https://doi.org/10.1089/jir.2022.0257","url":null,"abstract":"<p><p>Several inflammatory diseases are characterized by elevated T cell counts and high pro-inflammatory cytokine levels. Inhibiting T cell activity may reduce tissue damage associated with these diseases. Acthar<sup>®</sup> Gel has potent anti-inflammatory properties, yet little is known about its effect on T cells. This study compared the effects of Acthar, synthetic adrenocorticotropic hormone 1-24 (ACTH<sub>1-24</sub>) depot, and prednisolone in a murine model of T cell activation. Assessments of CD4<sup>+</sup> helper and CD8<sup>+</sup> cytotoxic T cells and plasma concentrations of interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α) were made following anti-CD3-activation. Acthar significantly reduced the number of activated CD4<sup>+</sup> and CD8<sup>+</sup> T cells at amounts comparable to synthetic ACTH<sub>1-24</sub> depot or prednisolone. However, Acthar reduced production of IFN-γ, IL-2, and TNF-α significantly more than the other drugs, suggesting that the <i>in vivo</i> immunomodulatory effects of Acthar on T cells are distinct from synthetic ACTH<sub>1-24</sub> depot or prednisolone.</p>","PeriodicalId":16261,"journal":{"name":"Journal of Interferon and Cytokine Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10039125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
There is no sensitive and effective method to predict radiation-induced myocardial damage (RIMD). The aim of this study was to explore effective plasma biomarkers for early prediction of RIMD after radiotherapy (RT) in lung cancer patients and in a rat model. Biomarker levels were measured in plasma samples collected before and after thoracic RT from 17 lung cancer patients. For the animal model, a single radiation dose of 40 Gy was delivered to the cardiac apex of female Wistar rats. Control rats received sham irradiation (0 Gy). Dynamic plasma biomarker detection and histopathological analysis to confirm RIMD were performed in rats up to 6 months after RT. In lung cancer patients, the plasma caspase-3 concentration was significantly increased after thoracic RT (P = 0.0479), with increasing but nonsignificant trends observed for caspase-1, CCL2, vascular endothelial growth factor (VEGF), interleukin-1β, and IL-6 (P > 0.05). Changes in caspase-3, VEGF, and IL-6 correlated significantly with mean heart dose (P < 0.05). In the RIMD rat model, caspase-1, caspase-3, CCl-2, VEGF, CCl-5, and TGF-β1 levels were significantly elevated in the first week post-RT (P < 0.05), which was earlier than pathological changes. Myocardial tissue of the RIMD rats also showed significant macrophage infiltration at 1 month (P < 0.01) and fibrosis at 6 months postradiation (P < 0.0001). Macrophage infiltration correlated significantly with plasma caspase-3, CCL2, CCL5, VEGF, and TGF-β1 levels from 3 weeks to 2 months post-RT. Increased plasma caspase-1, caspase-3, CCl-2, and VEGF levels were detected before RIMD-related pathological changes, indicating their clinical potential as biomarkers for early prediction of RIMD.
{"title":"Plasma Markers for Early Prediction of Radiation-Induced Myocardial Damage.","authors":"Yuanyuan Tao, Pei Li, Chenglong Zhao, Zhengshuai Mu, Yang Li, Shuanghu Yuan, Yuchun Wei","doi":"10.1089/jir.2022.0226","DOIUrl":"10.1089/jir.2022.0226","url":null,"abstract":"<p><p>There is no sensitive and effective method to predict radiation-induced myocardial damage (RIMD). The aim of this study was to explore effective plasma biomarkers for early prediction of RIMD after radiotherapy (RT) in lung cancer patients and in a rat model. Biomarker levels were measured in plasma samples collected before and after thoracic RT from 17 lung cancer patients. For the animal model, a single radiation dose of 40 Gy was delivered to the cardiac apex of female Wistar rats. Control rats received sham irradiation (0 Gy). Dynamic plasma biomarker detection and histopathological analysis to confirm RIMD were performed in rats up to 6 months after RT. In lung cancer patients, the plasma caspase-3 concentration was significantly increased after thoracic RT (<i>P</i> = 0.0479), with increasing but nonsignificant trends observed for caspase-1, CCL2, vascular endothelial growth factor (VEGF), interleukin-1β, and IL-6 (<i>P</i> > 0.05). Changes in caspase-3, VEGF, and IL-6 correlated significantly with mean heart dose (<i>P</i> < 0.05). In the RIMD rat model, caspase-1, caspase-3, CCl-2, VEGF, CCl-5, and TGF-β1 levels were significantly elevated in the first week post-RT (<i>P</i> < 0.05), which was earlier than pathological changes. Myocardial tissue of the RIMD rats also showed significant macrophage infiltration at 1 month (<i>P</i> < 0.01) and fibrosis at 6 months postradiation (<i>P</i> < 0.0001). Macrophage infiltration correlated significantly with plasma caspase-3, CCL2, CCL5, VEGF, and TGF-β1 levels from 3 weeks to 2 months post-RT. Increased plasma caspase-1, caspase-3, CCl-2, and VEGF levels were detected before RIMD-related pathological changes, indicating their clinical potential as biomarkers for early prediction of RIMD.</p>","PeriodicalId":16261,"journal":{"name":"Journal of Interferon and Cytokine Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10039122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mina Ghofrani Nezhad, Giti Jami, Omid Kooshkaki, Sajjad Chamani, Ali Naghizadeh
Cytokine storm refers to the overproduction of immune and inflammatory cells and their proteins (cytokines) [interleukin (IL)-1 and IL-6] causing acute respiratory distress syndrome in COVID-19. COVID-19 causes inflammatory reactions, and patients with COVID-19 had categorized as mild, severe, and critical after reviewing previous studies. Then, it is crucial to find immune-inflammatory indicators that might predict the disorder severity and the prognosis primarily for guiding medical therapy in the face of this unexpectedly developing unique infectious disease. Higher levels of IL-6 and IL-1 levels might be seen in patients with COVID-19 at each stage. In addition, IL-1-induced IL-6 assists in the synthesis of liver C-reactive protein (CRP) in acute phase responses. Recent studies suggested that IL-6 levels are an independent predictor of COVID-19 illness because they were significantly higher in patients with severe than with mild COVID-19 symptoms. Anakinra and tocilizumab (TCZ) are beneficial in lowing mortality in COVID-19 patients; however, information on their safety and efficacy is scarce. The aim of this study was to investigate the role of inflammatory cytokines (IL-1 and IL-6) as potential biomarkers in the different stages (mild, severe, and critical) of COVID-19. A systematic search during the years 2021-2022 using the keywords SARS-CoV-2, COVID-19, IL-6, IL-1, CRP, mild stage, severe stage, critical stage, cytokine storm, tocilizumab, and anakinra was performed in PubMed and Google Scholar databases. This study reviews studies that have investigated the role of high levels of these cytokines in the severity of the disease in patients with COVID-19 and the inhibitory function of TCZ and anakinra in preventing mechanical ventilation and patient mortality. According to the result, studies suggest that decreased innate immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in association with the production of inflammatory cytokines is the determining and driving function of COVID-19.
{"title":"The Role of Inflammatory Cytokines (Interleukin-1 and Interleukin-6) as a Potential Biomarker in the Different Stages of COVID-19 (Mild, Severe, and Critical).","authors":"Mina Ghofrani Nezhad, Giti Jami, Omid Kooshkaki, Sajjad Chamani, Ali Naghizadeh","doi":"10.1089/jir.2022.0185","DOIUrl":"https://doi.org/10.1089/jir.2022.0185","url":null,"abstract":"Cytokine storm refers to the overproduction of immune and inflammatory cells and their proteins (cytokines) [interleukin (IL)-1 and IL-6] causing acute respiratory distress syndrome in COVID-19. COVID-19 causes inflammatory reactions, and patients with COVID-19 had categorized as mild, severe, and critical after reviewing previous studies. Then, it is crucial to find immune-inflammatory indicators that might predict the disorder severity and the prognosis primarily for guiding medical therapy in the face of this unexpectedly developing unique infectious disease. Higher levels of IL-6 and IL-1 levels might be seen in patients with COVID-19 at each stage. In addition, IL-1-induced IL-6 assists in the synthesis of liver C-reactive protein (CRP) in acute phase responses. Recent studies suggested that IL-6 levels are an independent predictor of COVID-19 illness because they were significantly higher in patients with severe than with mild COVID-19 symptoms. Anakinra and tocilizumab (TCZ) are beneficial in lowing mortality in COVID-19 patients; however, information on their safety and efficacy is scarce. The aim of this study was to investigate the role of inflammatory cytokines (IL-1 and IL-6) as potential biomarkers in the different stages (mild, severe, and critical) of COVID-19. A systematic search during the years 2021-2022 using the keywords SARS-CoV-2, COVID-19, IL-6, IL-1, CRP, mild stage, severe stage, critical stage, cytokine storm, tocilizumab, and anakinra was performed in PubMed and Google Scholar databases. This study reviews studies that have investigated the role of high levels of these cytokines in the severity of the disease in patients with COVID-19 and the inhibitory function of TCZ and anakinra in preventing mechanical ventilation and patient mortality. According to the result, studies suggest that decreased innate immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in association with the production of inflammatory cytokines is the determining and driving function of COVID-19.","PeriodicalId":16261,"journal":{"name":"Journal of Interferon and Cytokine Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9682254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-04-01DOI: 10.1089/jir.2022.0014.correx
{"title":"<i>Correction to:</i> Elevated Level of Serum Interleukin-21 and Its Influence on Disease Activity in Anti-Neutrophil Cytoplasmic Antibodies Against Myeloperoxidase-Associated Vasculitis in the JICR by Junnan Xu et al. Journal of Interferon & Cytokine Research 2022;42(6): 290; DOI: 10.1089/jir.2022.0014.","authors":"","doi":"10.1089/jir.2022.0014.correx","DOIUrl":"https://doi.org/10.1089/jir.2022.0014.correx","url":null,"abstract":"","PeriodicalId":16261,"journal":{"name":"Journal of Interferon and Cytokine Research","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9300415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}