FcγR-induced production of superoxide and inflammatory cytokines is differentially regulated by SHIP through its influence on PI3K and/or Ras/Erk pathways

Phagocytosis of IgG-coated particles via FcγR is accompanied by the generation of superoxide and inflammatory cytokines, which can cause collateral tissue damage in the absence of regulation. Molecular mechanisms regulating these phagocytosis-associated events are not known. SHIP is an inositol phosphatase that downregulates PI3K-mediated activation events. Here, we have examined the role of SHIP in FcγR-induced production of superoxide and inflammatory cytokines. We report that primary SHIP-deficient bone marrow macrophages produce elevated levels of superoxide upon FcγR clustering. Analysis of the molecular mechanism revealed that SHIP regulates upstream Rac-GTP binding, an obligatory event for superoxide production. Likewise, SHIP-deficient macrophages displayed enhanced IL-1β and IL-6 production in response to FcγR clustering. Interestingly, whereas IL-6 production required activation of both PI3K and Ras/Erk pathways, IL-1β production was dependent only on Ras/Erk activation, suggesting that SHIP may also regulate the Ras/Erk pathway in macrophages. Consistently, SHIP-deficient macrophages displayed enhanced activation of Erk upon FcγR clustering. Inhibition of Ras/Erk or PI3K suppressed the enhanced production of IL-6 in SHIP-deficient macrophages. In contrast, inhibition of Ras/Erk, but not PI3K, suppressed IL-1β production in these cells. Together, these data demonstrate that SHIP regulates phagocytosis-associated events through the inhibition of PI3K and Ras/Erk pathways.

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Anti-Inflammatory Cytokines: Important Immunoregulatory Factors Contributing to Chemotherapy-Induced Gastrointestinal Mucositis

Chemotherapy Research and Practice ◽

10.1155/2012/490804 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 27

Author(s):

Masooma Sultani ◽

Andrea M. Stringer ◽

Joanne M. Bowen ◽

Rachel J. Gibson

Keyword(s):

Inflammatory Cytokines ◽

Proinflammatory Cytokines ◽

Molecular Mechanisms ◽

Tissue Injury ◽

Financial Burden ◽

Interleukin 1 ◽

Treatment Strategies ◽

Inflammatory Reactions ◽

Anti Inflammatory

“Mucositis” is the clinical term used to describe ulceration and damage of the mucous membranes of the entire gastrointestinal tract (GIT) following cytotoxic cancer chemotherapy and radiation therapy common symptoms include abdominal pain, bloating, diarrhoea, vomiting, and constipation resulting in both a significant clinical and financial burden. Chemotherapeutic drugs cause upregulation of stress response genes including NFκB, that in turn upregulate the production of proinflammatory cytokines such as interleukin-1β (IL-1β), Interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). These proinflammatory cytokines are responsible for initiating inflammation in response to tissue injury. Anti-inflammatory cytokines and specific cytokine inhibitors are also released to limit the sustained or excessive inflammatory reactions. In the past decade, intensive research has determined the role of proinflammatory cytokines in development of mucositis. However, a large gap remains in the knowledge of the role of anti-inflammatory cytokines in the setting of chemotherapy-induced mucositis. This critical paper will highlight current literature available relating to what is known regarding the development of mucositis, including the molecular mechanisms involved in inducing inflammation particularly with respect to the role of proinflammatory cytokines, as well as provide a detailed discussion of why it is essential to consider extensive research in the role of anti-inflammatory cytokines in chemotherapy-induced mucositis so that effective targeted treatment strategies can be developed.

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Molecular Mechanisms Regulating Resistance to the Akt Inhibitor Perifosine in Waldenstrom’s Macroglobulinemia, the Role of the ERK and PKC Pathways.

Blood ◽

10.1182/blood.v108.11.2416.2416 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2416-2416

Author(s):

Xavier Leleu ◽

Hai Ngo ◽

Xiaoying Jia ◽

Anne-Sophie Moreau ◽

Evdoxia Hatjiharisi ◽

...

Keyword(s):

Molecular Mechanisms ◽

Mek Inhibitor ◽

Pi3k Inhibitor ◽

Erk Pathway ◽

Waldenström’S Macroglobulinemia ◽

Akt Inhibitor ◽

Erk Activation ◽

Pi3k Inhibitor Ly294002 ◽

Akt Phosphorylation ◽

Waldenström's Macroglobulinemia

Abstract Background: We have previously demonstrated activity of the new Akt inhibitor perifosine (NSC 639966; Keryx, NY) in Waldenstrom’s Macroglobulinemia (WM). Perifosine induced complete inhibition of Akt phosphorylation along with induction of apoptosis in WM cells. However, MAPK pathways and PKC proteins were activated in response to perifosine. MAPK and PKC pathways are known to promote cell proliferation. Therefore, understanding the mechanism by which perifosine induces MEK/ERK and PKC activation is important to better understand the mechanisms of response/resistance to this novel agent in ongoing clinical trials. Methods: WM cell lines (BCWM.1, WM-WSU) were treated with perifosine or with the specific Akt inhibitor Triciribine (Biomol, PA). In addition, knockdown of Akt was performed using shRNA silencing techniques (lentivirus shRNA vector, Invitrogen, Ca). The following inhibitors were also used: PI3K inhibitor LY294002 (Calbiochem, CA) and MEK inhibitor (U0126, Calbiochem, CA). Inhibition of proliferation was measured using the MTT assay. Immunoblotting was performed at different time points. Results: Perifosine induced cytotoxicity in WM cells and induced MEK/ERK activation and pPKC activation in a dose and time dependent fashion. We then treated WM cells with perifosine in the presence or absence of the MEK inhibitor U0126 and demonstrated that the combination of the two agents induced significant synergistic activity. We sought to identify the molecular mechanism by which perifosine induces MEK/ERK activation. We demonstrated that the specific AKT inhibitor Triciribine inhibited AKT and induced cytotoxicity in WM cells in a similar fashion to perifosine. However, unlike perifosine, it did not enhance MEK/ERK activity. Similarly, using Akt shRNA, we demonstrated that, despite inhibition of Akt activation, MEK/ERK was not activated. These data indicate that the effect of perifosine on MEK/ERK pathway is not through a compensatory feedback mechanism of Akt inhibition as previously thought. Therefore, we hypothesized that the effect of perifosine on the MEK/ERK pathway is through modulation of upstream pathways, specifically PI3K, PKC and c-Raf/MEK pathways. We first demonstrated that the specific PI3K inhibitor LY294002 (25mM for 15 minutes) completely abrogated Akt phosphorylation, while inducing significant ERK activation, indicating that the effect of perifosine on MEK/ERK may be similar to that of LY294002. We also demonstrated that perifosine and LY294002 activated c-Raf and pan-pPKC at 4 hrs. Conclusion: Based on this, we believe that in the presence of perifosine, growth receptor stimulation leads to PLC and RTK activation, which induces PIP2 stimulation. PIP2 is upstream of PI3K and PKC. Given that PI3K is blocked by perifosine, PIP2 leads to activation of PKC, which then induces growth stimulation, and activation of c-Raf and downstream MEK/ERK. In addition, growth receptors may also activate Raf through the Ras/Raf/MEK pathway, independent of PKC. These studies provide a better understanding of molecular mechanisms that regulate resistance to perifosine. Future combinations of perifosine with MEK inhibitors or PKC inhibitors such as AZD6244 and Enzastaurin may overcome this resistance and induce significant activity in WM.

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Adenovirus Type 7 Induces Interleukin-8 Production via Activation of Extracellular Regulated Kinase 1/2

Journal of Virology ◽

10.1128/jvi.75.14.6450-6459.2001 ◽

2001 ◽

Vol 75 (14) ◽

pp. 6450-6459 ◽

Cited By ~ 46

Author(s):

M. J. Alcorn ◽

J. L. Booth ◽

K. M. Coggeshall ◽

J. P. Metcalf

Keyword(s):

Epithelial Cells ◽

Neutrophil Infiltration ◽

Adenovirus Type ◽

Mek Inhibitor ◽

Interleukin 8 ◽

Erk Pathway ◽

Erk Activation ◽

Extracellular Regulated Kinase ◽

Rapid Activation

ABSTRACT Infection with adenovirus serotype 7 (Ad7) frequently causes lower respiratory pneumonia and is associated with severe lung inflammation and neutrophil infiltration. Earlier studies indicated release of proinflammatory cytokines, specifically interleukin-8 (IL-8), by pulmonary epithelial cells following infection by Ad7. However, the mechanism of IL-8 induction by Ad7 is unclear. We have explored the role of the Ras/Raf/MEK/Erk pathway in the Ad7-associated induction of IL-8 using a model system of A549 epithelial cells. We found that Ad7 infection induced a rapid activation of epithelial cell-derived Erk. The MEK-specific inhibitors PD98059 and U0126 blocked Erk activation and release of IL-8 following infection with Ad7. Treatment with PD98059 is cytostatic and not cytotoxic, as treated cells regain the ability to phosphorylate Erk and secrete IL-8 after removal of the drug. The expression of a mutated form of Ras in A549 epithelial cells blocked the induction of IL-8 promoter activity, and MEK inhibitor blocked induction of IL-8 mRNA. These results suggest that the Ras/Raf/MEK/Erk pathway is necessary for the Ad7 induction of IL-8 and that induction occurs at the level of transcription. Further, the kinetics of Erk activation and IL-8 induction suggest that an early viral event, such as receptor binding, may be responsible for the observed inflammatory response.

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Role of ERK activation in H. pylori-induced disruption of cell-cell tight junctions

10.1101/2020.09.03.276600 ◽

2020 ◽

Author(s):

Amita Sekar ◽

Bow Ho

Keyword(s):

Tight Junction ◽

Barrier Function ◽

Cell Junction ◽

Erk Pathway ◽

Erk Activation ◽

Infected Cells ◽

H Pylori ◽

Tight Junction Disruption ◽

Cell Cell

AbstractBackgroundTight junctions, a network of claudins and other proteins, play an important role in maintaining barrier function and para-cellular permeability. H. pylori, the major etiological agent of various gastroduodenal diseases, is known to cause tight junction disruption. However, the molecular events that triggered cell-cell tight junction disruption in H. pylori-infected cells, remain largely elusive.Materials and MethodsTrans-epithelial electrical resistance (TEER) and FITC-Dextran permeability measurement were performed to determine the barrier function in H. pylori 88-3887-infected polarized MKN28 cells. For visualization of tight junction protein localization, immunofluorescence and immunoblotting techniques were used. To examine the role of ERK activation in tight junction disruption, U0126, a MEK inhibitor, was employed. To further support the study, computational analyses of H. pylori-infected primary gastric cells were carried out to decipher the transcriptomic changes.ResultsThe epithelial barrier of polarized MKN28 cells when infected with H. pylori displayed disruption of cell-cell junctions as shown by TEER & FITC-dextran permeability tests. Claudin-4 was shown to delocalize from host cytoplasm to nucleus in H. pylori-infected cells. In contrast, delocalization of claudin-4 was minimized when ERK activation was inhibited. Interestingly, transcriptomic analyses revealed the upregulation of genes associated with cell-junction assembly and ERK pathway forming a dense interacting network of proteins.ConclusionTaken together, evidence from this study indicates that H. pylori regulates ERK pathway triggering cell-cell junction disruption, contributing to host pathogenesis. It indicates the vital role of ERK in regulating key events associated with the development of H. pylori-induced gastroduodenal diseases.

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Mechanisms of innate immunity in pathogenesis of psoriasis: approaches to targeted therapy

Medical Immunology (Russia) ◽

10.15789/1563-0625-moi-1949 ◽

2020 ◽

Vol 22 (3) ◽

pp. 449-458

Author(s):

E. D. Merkushova ◽

E. M. Khasanova ◽

L. V. Gankovskaya

Keyword(s):

Innate Immunity ◽

Immune System ◽

Targeted Therapy ◽

Inflammatory Cytokines ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Pathological Process ◽

Climatic Conditions ◽

Keratinocyte Differentiation

Psoriasis is a chronic auto-inflammatory, genetically determined dermatosis, being multifactorial by origin, characterized by hyperproliferation of epidermis, affected keratinocyte differentiation and inflammatory reaction in dermis. The disease is characterized by a tendency to spread over the area of lesion, and involvement of articular tissue in the pathological process, which significantly affects the living standards of patients and causes their disability. There are many provoking factors that contribute to occurrence of psoriasis, or progression of existing psoriatic process in individuals with a genetic predisposition. These factors include adverse climatic conditions, skin trauma, exposure to ultraviolet light, burns, infections, etc.This review describes the role of innate immunity in pathogenesis of psoriasis, and describes in detail the mechanisms involved into induction of inflammation of PAMPs and DAMPs. In psoriasis, positively charged catelicidin is considered one of the most important DAMPs, which can form a complex with negatively charged cell polyanions-LL-37/auto-RNA and LL-37/auto-DNA. The interaction of PAMP/DAMP ligands with specific PRR receptors leads to signal activation of effector components of immune system, i.e., assembly of inflammasome complex, caspase activation, synthesis of inflammatory cytokines and processing of their immature forms. The review focuses on the role of TLRs under the conditions of physiological norm, which recognize danger signals and provide protection from pathogens and their timely elimination, and in development of pathological process. Activation of TLRs induces the production of pro-inflammatory cytokines, interferons and antimicrobial peptides, chemokines that support the development of psoriatic inflammation.In addition to TLRs, the mechanisms of involvement of inflammasomes in the development of psoriasis, which provides processing of mature forms of IL-1β and IL-18, are described in detail. Mature forms of these cytokines mediate the development of inflammation in psoriatic focus. In addition, processing of these cytokines by caspases using the positive feedback mechanism provides an additional signal to activate transcriptional activity of their genes and contributes to perpetuated inflammation.The review presents data confirming participation of inflammasomes in the pathogenesis of psoriasis. Much attention is paid to description of pharmacological inhibitors of inflammasomes, which in the future may be the drugs of choice for treatment of inflammatory diseases. The study of molecular mechanisms of the innate immune system will reveal new approaches to prognosis and development of targeted therapy for psoriasis.

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Preventive Role of Resveratrol Against Inflammatory Cytokines and Related Diseases

Current Pharmaceutical Design ◽

10.2174/1381612825666190410153307 ◽

2019 ◽

Vol 25 (12) ◽

pp. 1345-1371 ◽

Cited By ~ 6

Author(s):

Tanzir Rafe ◽

Parvez Ahmed Shawon ◽

Liyad Salem ◽

Nafij Imtiyaj Chowdhury ◽

Farjana Kabir ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Human Subjects ◽

Inflammatory Cells ◽

Host Cells ◽

Inflammatory Disorder ◽

Inflammatory Disorders ◽

Long Run

Background:Immunity is the ultimate barrier between foreign stimuli and a host cell. Unwanted immune responses can threaten the host cells and may eventually damage a vital organ. Overproduction of inflammatory cytokines may also lead to autoimmune diseases. Inflammatory cells and pro-inflammatory cytokines can eventually progress to renal, cardiac, brain, hepatic, pancreatic and ocular inflammation that can result in severe damage in the long run. Evidence also suggests that inflammation may lead to atherosclerosis, Alzheimer’s, hypertension, stroke, cysts and cancers.Methods:This study was designed to correlate the possible molecular mechanisms for inflammatory diseases and prevent biochemical changes owing to inflammatory cytokines by using Resveratrol. Therefore, we searched and accumulated very recent literature on inflammatory disorders and Resveratrol. We scoured PubMed, Scopus, Science Direct, PLoS One and Google Scholar to gather papers and related information.Results:Reports show that inflammatory diseases are very complex, as multiple cascade systems are involved; therefore, they are quite difficult to cure. However, our literature search also correlates some possible molecular interactions by which inflammation can be prevented. We noticed that Resveratrol is a potent lead component and has multiple activities against harmful inflammatory cytokines and related microRNA. Our study also suggests that the anti-inflammatory properties of Resveratrol have been highly studied on animal models, cell lines and human subjects and proven to be very effective in reducing inflammatory cell production and pro-inflammatory cytokine accumulation. Our tables and figures also demonstrate recent findings and possible preventive activities to minimize inflammatory diseases.Conclusion:This study would outline the role of harmful inflammatory cytokines as well as how they accelerate pathophysiology and progress to an inflammatory disorder. Therefore, this study might show a potential therapeutic value of using Resveratrol by health professionals in preventing inflammatory disorders.

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Atypical Protein Kinase Cs Promote CSF-1-Dependent Erk Activation and Proliferation in Myeloid Cells.

Blood ◽

10.1182/blood.v108.11.4227.4227 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4227-4227 ◽

Cited By ~ 1

Author(s):

Angel W. Lee

Keyword(s):

Drug Targets ◽

Phorbol Esters ◽

Myeloid Cells ◽

Dominant Negative ◽

Erk Pathway ◽

Erk Activation ◽

Cell Biol ◽

Pkc Inhibitors

Abstract Macrophages are integral components of the innate immune system and essential players in inflammation. Enhanced macrophage numbers underlie these pathological states. Colony stimulating factor-1 (CSF-1) is the major physiological regulator of proliferation and survival of cells of the monocyte/macrophage lineage. CSF-1 binds to a receptor tyrosine kinase, the CSF-1 receptor (CSF-1R). CSF-1 and CSF-1R have emerged as drug targets in several diseases where inflammation is a critical component, e.g. breast cancer and rheumatoid arthritis. Multiple pathways are activated downstream of the CSF-1R; however, it is not clear which of these pathways regulate proliferation and survival. Atypical PKCs (aPKCs) are implicated in cell proliferation and survival. They include the isoforms PKCζ and PKCλ/ι. Unlike the classical and novel PKCs, aPKCs are insensitive to Ca2+ and phorbol esters. In this study, we investigated the role of aPKCs in CSF-1-mediated proliferation in myeloid cells. CSF-1 is a proliferation and survival factor for 32D.R cells, a myeloid progenitor cell line transfected with the CSF-1R. Western blotting shows that PKCα, PKCδ, PKCε and PKCζ/λ/I are expressed in 32D.R. Based on studies with PKC inhibitors that have different specificities towards aPKCs (GF109203X, Ro-31-8220, Go6983 and a Myr-PKCζ peptide), maximal CSF-1-dependent proliferation in 32D.R cells appears to depend on the activity of either aPKCs or PKCε. Using phospho-specific antibodies that detect the activation state of PKCζ as well as in vitro kinase assays, we showed that CSF-1 activates aPKCs in 32D.R and bone marrow derived macrophages. In contrast, CSF-1-induced activation of PKCε was not observed. We next asked how aPKC affects CSF-1 signaling. PKCζ promotes activation of the MEK-Erk pathway in different cell types (Corbit, K.C. et al. Mol. Cell. Biol. 20, 5392). In 32D.R cells, treatment with the MEK inhibitor, U0126, reduced CSF-1-provoked proliferation by 60–70%, consistent with the inhibition observed with PKC inhibitors. Previous work from our lab showed that CSF-1 activates the Erk pathway through A-Raf and not Raf-1 (Lee and States, Mol. Cell. Biol. 18, 6779). We found that aPKC inhibitors do not affect CSF-1 induced Ras and A-Raf activity but markedly reduce MEK and Erk activity, implying that aPKC inputs into the CSF-1 Erk pathway at the level of MEK. Transient transfections with dominant-negative and constitutively active (CA) PKCζ confirmed that aPKC promotes CSF-1-induced Erk activation. aPKC inhibition does not affect CSF-1-stimulated Akt activation. To investigate the role of PKCζ in CSF-1-dependent proliferation, we established stable 32D.R mass populations overexpressing wildtype (WT) or CA PKCζ at levels 2-fold above endogenous. Comparing cells expressing CA-PKCζ to WT-PKCζ, the EC50 for CSF-1-dependent proliferation and the cell doubling time at maximal CSF-1 concentration were both reduced, consistent with a role for PKCζ in CSF-1 dependent proliferation. We will use our stable cell lines to elucidate the pathways modulated by PKCζ. Altogether, our results identify atypical PKCs as new targets of CSF-1 signaling.

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The Role of Protein Tyrosine Phosphatase, Shp2, in FLT3-ITD-Induced Leukemogenesis.

Blood ◽

10.1182/blood.v112.11.1804.1804 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1804-1804

Author(s):

Sarah C Nabinger ◽

Seiji Fukuda ◽

Reuben Kapur ◽

Rebecca Chan

Keyword(s):

Protein Tyrosine Phosphatase ◽

Molecular Mechanisms ◽

Tyrosine Phosphatase ◽

Dependent Manner ◽

Erk Activation ◽

Protein Tyrosine ◽

Knock Down ◽

Mammalian Expression ◽

Tandem Duplications

Abstract Internal tandem duplications of the FMS-like receptor tyrosine kinase (FLT3-ITDs), an in-fame insertion of several amino acids within the juxtamembrane domain, are present in 25% of acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3-ITDs induce FLT3 ligand (FL)-independent hyperactivation of Erk and promiscuous activation of STAT5; however, the molecular mechanisms underlying aberrant activation of these signaling molecules is largely unknown. Tyrosine 599 (Y599) of WT FLT3 recruits the protein tyrosine phosphatase, Shp2, upon stimulation with FL, resulting Erk activation. In several FLT3-ITDs, including N51-FLT3 and N73-FLT3, Y599 is duplicated. These findings led us to hypothesize that increased recruitment of Shp2 to N51-FLT3 or N73- FLT3, via Y599, results in enhanced Shp2 activation and contributes to N51-FLT3- and N73-FLT3-induced cellular hyperproliferation, Erk hyperactivation, and promiscuous STAT5 activation. Using Baf3 cells stably expressing WT FLT3, N51-FLT3, or N73- FLT3, co-immunoprecipitation assays demonstrated that Shp2 is phosphorylated and associates with WT FLT3 in a FL-dependent manner. However, in contrast, Shp2 is constitutively hyperphosphorylated and associated with FLT3-N51 and FLT3-N73 independent of FL stimulation. To investigate the functional role of Shp2 in Flt3-ITD-induced leukemogenesis, Baf3 cells expressing WT FLT3, N51-FLT3, or N73-FLT3 were transfected with a mammalian expression vector encoding a U6 polymerase III– directed Shp2-specific short-hairpin RNA (shRNA) or a scrambled shRNA and selected in puromycin. Western blot analysis revealed significant reduction of Shp2 expression by the Shp2-specific shRNA and no change in Shp2 expression by the scrambled shRNA in all cell lines. Upon knock-down of Shp2 in Baf3/WT-FLT3 cells, proliferation was minimally reduced based on thymidine incorporation assays; however, knock-down of Shp2 in Baf3/N51-FLT3 and Baf3/N73-FLT3 cells significantly reduced proliferation, both at baseline and in response to FL stimulation. Collectively, these data suggest that constitutive recruitment of Shp2 to N51-FLT3 and N73-FLT3 contributes to the FLT3- ITD-induced hyperproliferative phenotype and imply that inhibition of Shp2 function may provide a novel therapeutic approach to FLT3-ITD-bearing leukemias.

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Thiol regulation of pro-inflammatory cytokines and innate immunity: protein S-thiolation as a novel molecular mechanism

Biochemical Society Transactions ◽

10.1042/bst0391268 ◽

2011 ◽

Vol 39 (5) ◽

pp. 1268-1272 ◽

Cited By ~ 20

Author(s):

Lucia Coppo ◽

Pietro Ghezzi

Keyword(s):

Inflammatory Cytokines ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Protein S ◽

Protein Thiol ◽

Cytokine Inhibitors ◽

Key Enzyme ◽

And Oxidative Stress ◽

Pro Inflammatory Cytokines

Inflammation or inflammatory cytokines and oxidative stress have often been associated, and thiol antioxidants, particularly glutathione, have often been seen as possible anti-inflammatory mediators. However, whereas several cytokine inhibitors have been approved for drug use in chronic inflammatory diseases, this has not happened with antioxidant molecules. We outline the complexity of the role of protein thiol–disulfide oxidoreduction in the regulation of immunity and inflammation, the underlying molecular mechanisms (such as protein glutathionylation) and the key enzyme players such as Trx (thioredoxin) or Grx (glutaredoxin).

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Supervillin contributes to LPS-induced inflammatory response in THP-1 cell-derived macrophages

10.21203/rs.3.rs-455521/v1 ◽

2021 ◽

Author(s):

Jun Zhou ◽

Yuhui Que ◽

Lihua Pan ◽

Xu Li ◽

Chao Zhu ◽

...

Keyword(s):

Inflammatory Response ◽

Protein Expression ◽

Mrna Expression ◽

Inflammatory Cytokines ◽

Molecular Mechanisms ◽

Actin Binding ◽

Tnf Α ◽

Mrna And Protein Expression ◽

Underlying Mechanisms

Abstract Supervillin (SVIL), the largest member of villin/gelsolin family, is an actin-binding and membrane-associated protein, that can also be localized to the nucleus. It has been reported that the mRNA expression of SVIL in neutrophils could be increased by lipopolysaccharide (LPS), but the underlying mechanisms remain unknown. Moreover, SVIL was also observed to be involved in the regulation of macrophages’ movement. However, it is not clear whether SVIL is involved in the LPS-induced inflammatory response in macrophages. This work was to investigate the underlying molecular mechanisms of LPS regulating SVIL expression in macrophages and hence the possible role of SVIL in LPS-induced inflammation. Our data showed that in THP-1-derived macrophages, LPS stimulation significantly increased SVIL mRNA and protein expression. Inhibition of TLR4 by Resatorvid (Res) completely reversed the expression of SVIL and inflammatory cytokines (IL-6, IL-1β and TNF-α) induced by LPS. Additionally, ERK1/2 and NF-κB inhibitors (U0126 and BAY) significantly reduced SVIL and IL-6, IL-1β & TNF-α expression. Furthermore, down-regulation of SVIL by SVIL-specific shRNA significantly attenuated the expression of IL-6, IL-1β & TNF-α induced by LPS. Taken together, as a downstream molecule of TLR4/NF-κB and ERK1/2, SVIL was involved in the inflammatory response of LPS-induced elevated IL-6, IL-1β and TNF-α in macrophages.

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