Activation of the MKK3-p38-MK2-ZFP36 axis by coronavirus infection restricts the upregulation of AU-rich element-containing transcripts in proinflammatory response

2022 ◽  
Author(s):  
Shumin Li ◽  
Siying Liu ◽  
Rui Ai Chen ◽  
Mei Huang ◽  
To Sing Fung ◽  
...  
Keyword(s):  
Map Kinase ◽  
Proinflammatory Cytokines ◽  
Binding Protein ◽  
Regulatory Role ◽  
Proinflammatory Response ◽  
Cytokines And Chemokines ◽  
Coronavirus Infection ◽  
Anti Inflammatory ◽  
Coronavirus Infections ◽  
In Cells

Coronavirus infections induce the expression of multiple proinflammatory cytokines and chemokines. We have previously shown that in cells infected with gammacoronavirus infectious bronchitis virus (IBV), interleukin 6 (IL-6) and IL-8 were drastically upregulated, and the MAP kinase p38 and the integrated stress response pathways were implicated in this process. In this study, we report that coronavirus infection activates a negative regulatory loop that restricts the upregulation of a number of proinflammatory genes. As revealed by the initial transcriptomic and subsequent validation analyses, the anti-inflammatory adenine-uridine (AU)-rich element (ARE)-binding protein, Zinc finger protein 36 (ZFP36) and its related family members were upregulated in cells infected with IBV and three other coronaviruses, alphacoronaviruses porcine epidemic diarrhea virus (PEDV) and human coronavirus 229E (HCoV-229E), and betacoronavirus HCoV-OC43, respectively. Characterization of the functional roles of ZFP36 during IBV infection demonstrated that ZFP36 promoted the degradation of transcripts coding for IL-6, IL-8, dual-specificity phosphatase 1 (DUSP1), prostaglandin-endoperoxide synthase 2 (PTGS2) and TNF-α-induced protein 3 (TNFAIP3), through binding to AREs in these transcripts. Consistently, knockdown and inhibition of JNK and p38 kinase activities reduced the expression of ZFP36, as well as the expression of IL-6 and IL-8. On the contrary, overexpression of mitogen-activated protein kinase kinase 3 (MKK3) and MAPKAP kinase-2 (MK2), the upstream and downstream kinases of p38, respectively, increased the expression of ZFP36 and decreased the expression of IL-8. Taken together, this study reveals an important regulatory role of the MKK3-p38-MK2-ZFP36 axis in coronavirus infection-induced proinflammatory response. Importance Excessive and uncontrolled induction and release of proinflammatory cytokines and chemokines, the so-called cytokine release syndrome (CRS), would cause life-threatening complications and multiple organ failure in severe coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and COVID-19. This study reveals that coronavirus infection also induces the expression of ZFP36, an anti-inflammatory ARE-binding protein, promoting the degradation of ARE-containing transcripts coding for IL-6 and IL-8 as well as a number of other proteins related to inflammatory response. Furthermore, the p38 MAP kinase, its upstream kinase MKK3 and downstream kinase MK2 were shown to play a regulatory role in upregulation of ZFP36 during coronavirus infection cycles. This MKK3-p38-MK2-ZFP36 axis would constitute a potential therapeutic target for severe coronavirus infections.

scholarly journals Campylobacter jejuni-Induced Cytokine Responses in Avian Cells

2005 ◽  
Vol 73 (4) ◽  
pp. 2094-2100 ◽  
Author(s):  
Chris K. Smith ◽  
Pete Kaiser ◽  
Lisa Rothwell ◽  
Tom Humphrey ◽  
Paul A. Barrow ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Proinflammatory Cytokines ◽  
Disease Process ◽  
Avian Host ◽  
Macrophage Cell ◽  
Proinflammatory Response ◽  
Cytokines And Chemokines ◽  
Cytokine Responses ◽  
Chick Kidney

ABSTRACT Campylobacter jejuni is a major cause of human inflammatory enteritis. During the course of human disease numerous proinflammatory cytokines are produced. Little is known, however, about the cytokine responses produced during the interaction of this bacterium with the avian host. Campylobacter has been considered a commensal of the avian host. Any differences in innate responses to this pathogen between the human and avian hosts should lead to a greater understanding of the disease process in humans. We have demonstrated expression of proinflammatory cytokines and chemokines in response to Campylobacter infection in avian primary chick kidney cells and the avian macrophage cell line HD11. The data indicate that Campylobacter can stimulate the avian host in a proinflammatory manner. The data strongly suggest that the lack of pathology in vivo is not due to an inability of Campylobacter to stimulate a proinflammatory response from avian cells.

scholarly journals Is Saffron Able to Prevent the Dysregulation of Retinal Cytokines Induced by Ocular Hypertension in Mice?

2021 ◽  
Vol 10 (21) ◽  
pp. 4801
Author(s):  
José A. Fernández-Albarral ◽  
Miguel A. Martínez-López ◽  
Eva M. Marco ◽  
Rosa de Hoz ◽  
Beatriz Martín-Sánchez ◽  
...  
Keyword(s):  
Ocular Hypertension ◽  
Proinflammatory Cytokines ◽  
Control Group ◽  
Chemokine Production ◽  
Cytokines And Chemokines ◽  
Saffron Extract ◽  
Anti Inflammatory ◽  
Contralateral Eye ◽  
Laser Induction ◽  
Endothelial Growth Factor

Cytokine- and chemokine-mediated signalling is involved in the neuroinflammatory process that leads to retinal ganglion cell (RGC) damage in glaucoma. Substances with anti-inflammatory properties could decrease these cytokines and chemokines and thus prevent RGC death. The authors of this study analysed the anti-inflammatory effect of a hydrophilic saffron extract standardized to 3% crocin content, focusing on the regulation of cytokine and chemokine production, in a mouse model of unilateral laser-induced ocular hypertension (OHT). We demonstrated that following saffron treatment, most of the concentration of proinflammatory cytokines (IL-1β, IFN-γ, TNF-α, and IL-17), anti-inflammatory cytokines (IL-4 and IL-10), Brain-derived Neurotrophic Factor (BDNF), Vascular Endothelial Growth Factor (VEGF), and fractalkine were unaffected in response to laser-induced OHT in both the OHT eye and its contralateral eye. Only IL-6 levels were significantly increased in the OHT eye one day after laser induction compared with the control group. These results differed from those observed in animals subjected to unilateral OHT and not treated with saffron, where changes in cytokine levels occurred in both eyes. Therefore, saffron extract regulates the production of proinflammatory cytokines, VEGF, and fractalkine induced by increasing intraocular pressure (IOP), protecting the retina from inflammation. These results indicate that saffron could be beneficial in glaucoma by helping to reduce the inflammatory process.

scholarly journals Proactive anti-inflammatory and anticoagulant therapy in the treatment of advanced stages of novel coronavirus infection (COVID-19). Case Series and Study Design: COLchicine versus ruxolitinib and secukinumab in open prospective randomIzed trial (COLORIT)

Kardiologiia ◽  
2020 ◽  
Vol 60 (9) ◽  
pp. 4-21
Author(s):  
V. Yu. Mareev ◽  
Ya. A. Orlova ◽  
E. P. Pavlikova ◽  
Z. A. Akopyan ◽  
S. T. Matskeplishvili ◽  
...  
Keyword(s):  
Case Series ◽  
Pathological Process ◽  
Janus Kinase ◽  
Interleukin 17 ◽  
Small Vessels ◽  
Cytokines And Chemokines ◽  
Clinical Series ◽  
Advanced Stages ◽  
Coronavirus Infection ◽  
Anti Inflammatory

The article is devoted to the treatment of the new coronavirus infection (COVID-19) in the advanced stages of the disease. The types of response of the immune system to the viral load of SARS-CoV-2 with the start of the inflammation process are considered. The situation is analyzed in detail in which the growing autoimmune inflammation (up to the development of a "cytokine storm") affects not only the pulmonary parenchyma, but also the endothelium of the small vessels of the lungs. Simultaneous damage to the alveoli and microthrombosis of the pulmonary vessels are accompanied by a progressive impairment of gas exchange, the development of acute respiratory distress syndrome, the treatment of which, even with the use of invasive ventilation, is ineffective and does not really change the prognosis of patients with COVID-19. In order to interrupt the pathological process at the earliest stages of the disease, the necessity of proactive anti-inflammatory therapy in combination with active anticoagulation treatment is substantiated. The results of the first randomized studies on the use of inhibitors of pro-inflammatory cytokines and chemokines (interleukin-6 (tocilizumab), interleukin-17 (secukinumab), Janus kinase blockers, through which the signal is transmitted to cells (ruxolitinib)), which have potential in the early treatment of COVID- 19. The use of a well-known anti-inflammatory drug colchicine (which is used for gout treatment) in patients with COVID-19 is considered. The design of the original COLORIT comparative study on the use of colchicine, ruxolitinib and secukinumab in the treatment of COVID-19 is presented. Clinical series presented, illustrated early anti-inflammatory therapy together with anticoagulants in patients with COVID-19 and the dangers associated with refusing to initiate such therapy on time.

The role of cytokines, chemokines and growth factors in extraction socket healing

2021 ◽  
Vol 26 (1) ◽  
pp. 58-63
Author(s):  
N. L. Erokina ◽  
A. V. Lepilin ◽  
A. Yu. Mironov ◽  
N. B. Zakharova ◽  
S. B. Fishtchev
Keyword(s):  
Growth Factors ◽  
Proinflammatory Cytokines ◽  
Biological Fluids ◽  
Tissue Remodelling ◽  
Cytokine Network ◽  
Laboratory Findings ◽  
Extraction Socket ◽  
Cytokines And Chemokines ◽  
Socket Healing ◽  
Anti Inflammatory

Relevance. Reparative processes in the extraction socket include hemostasis, inflammation, proliferation and tissue remodelling. These processes are caused by mediators which determine interactions in the immunoregulatory, cytokine network. After the tooth extraction, pro- and anti-inflammatory mediators are unbalanced. The number of macrophages, lymphocytes, neutrophils releasing lysosomal enzymes increases in the surrounding tissues, and it leads to cleaning of the extraction socket from the damaged tissues and microorganisms. The growth factors are of great importance for reparative processes. The level of cytokines, chemokines and growth factors in biological fluids is the assessment criterium of various physiological and pathological processes and effectiveness of the treatment procedures. Purpose – to assess the activity of the wound healing processes by studying the level of cytokines/ chemokines and growth factors in the extraction socket. Materials and methods. The data received on examination of 40 patients was used in the study. 20 of the patients had their teeth extracted for chronic periodontitis and the socket healing was studied by clinical and laboratory findings (seven mediators of immunoregulatory processes were studied). The comparison group consisted of 20 subjects without periodontal pathology. Results. Clinical data, typical for the normal socket healing, are characterized by the certain content of immunoregulatory mediators (IL1β and IL6 – proinflammatory cytokines, IL8 and MCP1 – chemokines, RAIL1 – anti-inflammatory cytokine, VEGF and TGFβ1- growth factors). The content of proinflammatory cytokines and chemokines was detected to increase in the socket on the first day after the extraction, which indicates the activity of the local inflammatory process. The level of RAIL 1 and VEGF and TGFβ1 growth factors increases in the extraction socket five days later. Conclusion. The post-surgical activity of the inflammatory and regenerative processes in the tissues is revealed by the level of cytokines/ chemokines on the first day after surgery and the level of growth factors and RAIL1 in the socket discharge on the fifth day after surgery.

Anti-inflammatory response is associated with mortality and severity of infection in sepsis

2005 ◽  
Vol 288 (4) ◽  
pp. L633-L640 ◽  
Author(s):  
Alix Ashare ◽  
Linda S. Powers ◽  
Noah S. Butler ◽  
Kevin C. Doerschug ◽  
Martha M. Monick ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Proinflammatory Cytokines ◽  
Murine Model ◽  
Bacterial Load ◽  
Cecal Ligation ◽  
Proinflammatory Response ◽  
Inflammatory Phase ◽  
Anti Inflammatory ◽  
Soluble Tnf Receptor

Using a murine model of sepsis, we found that the balance of tissue pro- to anti-inflammatory cytokines directly correlated with severity of infection and mortality. Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Liver tissue was analyzed for levels of IL-1β, IL-1 receptor antagonist (IL-1ra), tumor necrosis factor (TNF)-α, and soluble TNF receptor 1 by ELISA. Bacterial DNA was measured using quantitative real-time PCR. After CLP, early predominance of proinflammatory cytokines (6 h) transitioned to anti-inflammatory predominance at 24 h. The elevated anti-inflammatory cytokines were mirrored by increased tissue bacterial levels. The degree of anti-inflammatory response compared with proinflammatory response correlated with the bacterial concentration. To modulate the timing of the anti-inflammatory response, mice were treated with IL-1ra before CLP. This resulted in decreased proinflammatory cytokines, earlier bacterial load, and increased mortality. These studies show that the initial tissue proinflammatory response to sepsis is followed by an anti-inflammatory response. The anti-inflammatory phase is associated with increased bacterial load and mortality. These data suggest that it is the timing and magnitude of the anti-inflammatory response that predicts severity of infection in a murine model of sepsis.

scholarly journals Splenectomy exacerbates lung injury after ischemic acute kidney injury in mice

2011 ◽  
Vol 301 (4) ◽  
pp. F907-F916 ◽  
Author(s):  
Ana Andrés-Hernando ◽  
Christopher Altmann ◽  
Nilesh Ahuja ◽  
Miguel A. Lanaspa ◽  
Raphael Nemenoff ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Lung Injury ◽  
Proinflammatory Cytokines ◽  
Kidney Injury ◽  
Myeloperoxidase Activity ◽  
Proinflammatory Response ◽  
Sham Surgery ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine

Patients with acute kidney injury (AKI) have increased serum proinflammatory cytokines and an increased occurrence of respiratory complications. The aim of the present study was to examine the effect of renal and extrarenal cytokine production on AKI-mediated lung injury in mice. C57Bl/6 mice underwent sham surgery, splenectomy, ischemic AKI, or ischemic AKI with splenectomy and kidney, spleen, and liver cytokine mRNA, serum cytokines, and lung injury were examined. The proinflammatory cytokines IL-6, CXCL1, IL-1β, and TNF-α were increased in the kidney, spleen, and liver within 6 h of ischemic AKI. Since splenic proinflammatory cytokines were increased, we hypothesized that splenectomy would protect against AKI-mediated lung injury. On the contrary, splenectomy with AKI resulted in increased serum IL-6 and worse lung injury as judged by increased lung capillary leak, higher lung myeloperoxidase activity, and higher lung CXCL1 vs. AKI alone. Splenectomy itself was not associated with increased serum IL-6 or lung injury vs. sham. To investigate the mechanism of the increased proinflammatory response, splenic production of the anti-inflammatory cytokine IL-10 was determined and was markedly upregulated. To confirm that splenic IL-10 downregulates the proinflammatory response of AKI, IL-10 was administered to splenectomized mice with AKI, which reduced serum IL-6 and improved lung injury. Our data demonstrate that AKI in the absence of a counter anti-inflammatory response by splenic IL-10 production results in an exuberant proinflammatory response and lung injury.

scholarly journals Doxycycline Is Anti-Inflammatory and Inhibits Staphylococcal Exotoxin-Induced Cytokines and Chemokines

2003 ◽  
Vol 47 (11) ◽  
pp. 3630-3633 ◽  
Author(s):  
Teresa Krakauer ◽  
Marilyn Buckley
Keyword(s):  
Cell Proliferation ◽  
Proinflammatory Cytokines ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
T Cell Proliferation ◽  
Peripheral Blood Mononuclear ◽  
Cytokines And Chemokines ◽  
Blood Mononuclear Cells ◽  
Anti Inflammatory ◽  
Pathogenic Effects

ABSTRACT Proinflammatory cytokines mediate the toxic effect of superantigenic staphylococcal exotoxins (SE). Doxycycline inhibited SE-stimulated T-cell proliferation and production of cytokines and chemokines by human peripheral blood mononuclear cells. These results suggest that the antibiotic doxycycline has anti-inflammatory effects and is therapeutically useful for mitigating the pathogenic effects of SE.

scholarly journals Anti-Inflammatory Effects of Lagerstroemia ovalifolia Teijsm. & Binn. in TNFα/IFNγ-Stimulated Keratinocytes

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Han-Sol Lee ◽  
Jin-Hyub Paik ◽  
Ok-Kyoung Kwon ◽  
Imam Paryanto ◽  
Prasetyawan Yuniato ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Proinflammatory Cytokines ◽  
Inflammatory Diseases ◽  
Hacat Cells ◽  
Necrosis Factor Alpha ◽  
Monocyte Chemoattractant Protein 1 ◽  
Cytokines And Chemokines ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

Ethnopharmacological Relevance. Atopic dermatitis is a chronic inflammatory skin disease. Lagerstroemia ovalifolia Teijsm. & Binn. (LO) has traditionally been used as an herbal medicine for anti-inflammatory diseases. The effect of LO on atopic dermatitis has not been verified scientifically. We investigated the effects of CHCl3 fraction number 5 of LO (LOC) on atopic dermatitis through cell-based experiments. HaCaT cells were treated with tumor necrosis factor-alpha (TNFα)/interferon-gamma (IFNγ) to induce an inflammatory reaction. Proinflammatory cytokines, interleukin- (IL-) 6, IL-8, and IL-1β and chemokines such as thymus and activation-regulated chemokine (TARC/CCL17), monocyte chemoattractant protein 1 (MCP1/CCL2), and macrophage-derived chemokine (MDC/CCL22) were measured by RT-PCR and ELISA. In addition, the degree of phosphorylation and activation of JAK/STAT1, PI3K/AKT, and nuclear factor-kappa B (NF-κB) were measured by western blot and luciferase assays. The production of inflammatory cytokines and chemokines and activation of the JAK/STAT1, PI3K/AKT, and NF-κB pathways were induced by TNFα/IFNγ in HaCaT cells. Under these conditions, LOC treatment inhibited the production of targeted cytokines and chemokines and decreased the phosphorylation and activation of JAK/STAT1, PI3K/AKT, and NF-κB. These results suggest that LOC reduces the production of proinflammatory cytokines and chemokines by suppressing the JAK/STAT1, PI3K/AKT, and NF-κB pathways. Therefore, LOC may have potential as a drug for atopic dermatitis.

scholarly journals The Immune System in Tissue Environments Regaining Homeostasis after Injury: Is “Inflammation” Always Inflammation?

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Onkar P. Kulkarni ◽  
Julia Lichtnekert ◽  
Hans-Joachim Anders ◽  
Shrikant R. Mulay
Keyword(s):  
Immune System ◽  
Proinflammatory Cytokines ◽  
Inflammatory Mediators ◽  
Innate Immune System ◽  
Clinical Signs ◽  
Innate Immune ◽  
Cytokines And Chemokines ◽  
Anti Inflammatory ◽  
Tissue Injuries

Inflammation is a response to infections or tissue injuries. Inflammation was once defined by clinical signs, later by the presence of leukocytes, and nowadays by expression of “proinflammatory” cytokines and chemokines. But leukocytes and cytokines often have rather anti-inflammatory, proregenerative, and homeostatic effects. Is there a need to redefine “inflammation”? In this review, we discuss the functions of “inflammatory” mediators/regulators of the innate immune system that determine tissue environments to fulfill the need of the tissue while regaining homeostasis after injury.

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