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1.
Cell Rep Med ; 4(1): 100899, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36652908

RESUMO

The non-canonical inflammasome sensor caspase-11 and gasdermin D (GSDMD) drive inflammation and pyroptosis, a type of immunogenic cell death that favors cell-mediated immunity (CMI) in cancer, infection, and autoimmunity. Here we show that caspase-11 and GSDMD are required for CD8+ and Th1 responses induced by nanoparticulate vaccine adjuvants. We demonstrate that nanoparticle-induced reactive oxygen species (ROS) are size dependent and essential for CMI, and we identify 50- to 60-nm nanoparticles as optimal inducers of ROS, GSDMD activation, and Th1 and CD8+ responses. We reveal a division of labor for IL-1 and IL-18, where IL-1 supports Th1 and IL-18 promotes CD8+ responses. Exploiting size as a key attribute, we demonstrate that biodegradable poly-lactic co-glycolic acid nanoparticles are potent CMI-inducing adjuvants. Our work implicates ROS and the non-canonical inflammasome in the mode of action of polymeric nanoparticulate adjuvants and establishes adjuvant size as a key design principle for vaccines against cancer and intracellular pathogens.


Assuntos
Inflamassomos , Nanopartículas , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Caspases/metabolismo , Interleucina-1/metabolismo
2.
Proc Natl Acad Sci U S A ; 120(5): e2213777120, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36693106

RESUMO

The accrual of cytosolic DNA leads to transcription of type I IFNs, proteolytic maturation of the IL-1 family of cytokines, and pyroptotic cell death. Caspase-1 cleaves pro-IL1ß to generate mature bioactive cytokine and gasdermin D which facilitates IL-1 release and pyroptotic cell death. Absent in melanoma-2 (AIM2) is a sensor of dsDNA leading to caspase-1 activation, although in human monocytes, cGAS-STING acting upstream of NLRP3 mediates the dsDNA-activated inflammasome response. In healthy human keratinocytes, AIM2 is not expressed yet caspase-1 is activated by the synthetic dsDNA mimetic poly(dA:dT). Here, we show that this response is not mediated by either AIM2 or the cGAS-STING-NLRP3 pathway and is instead dependent on NLRP1. Poly(dA:dT) is unique in its ability to activate NLRP1, as conventional linear dsDNAs fail to elicit NLRP1 activation. DsRNA was recently shown to activate NLRP1 and prior work has shown that poly(dA:dT) is transcribed into an RNA intermediate that stimulates the RNA sensor RIG-I. However, poly(dA:dT)-dependent RNA intermediates are insufficient to activate NLRP1. Instead, poly(dA:dT) results in oxidative nucleic acid damage and cellular stress, events which activate MAP3 kinases including ZAKα that converge on p38 to activate NLRP1. Collectively, this work defines a new activator of NLRP1, broadening our understanding of sensors that recognize poly(dA:dT) and advances the understanding of the immunostimulatory potential of this potent adjuvant.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Citocinas/metabolismo , DNA/metabolismo , Caspase 1/metabolismo , RNA/metabolismo , Queratinócitos/metabolismo , Interleucina-1/metabolismo , Proteínas NLR/metabolismo
3.
Viruses ; 15(1)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36680273

RESUMO

African swine fever (ASF) is a hemorrhagic viral disease of domestic pigs and wild suids (all Sus scrofa) caused by the ASF virus (ASFV). The disease is spreading worldwide without control, threatening pig production due to the absence of licensed vaccine or commercially available treatments. A thorough understanding of the immunopathogenic mechanisms behind ASFV infection is required to better fight the disease. Cytokines are small, non-structural proteins, which play a crucial role in many aspects of the immune responses to viruses, including ASFV. Infection with virulent ASFV isolates often results in exacerbated immune responses, with increased levels of serum pro-inflammatory interleukins (IL-1α, IL-1ß, IL-6), TNF and chemokines (CCL2, CCL5, CXCL10). Increased levels of IL-1, IL-6 and TNF are often detected in several tissues during acute ASFV infections and associated with lymphoid depletion, hemorrhages and oedemas. IL-1Ra is frequently released during ASFV infection to block further IL-1 activity, with its implication in ASFV immunopathology having been suggested. Increased levels of IFN-α and of the anti-inflammatory IL-10 seem to be negatively correlated with animal survival, whereas some correlation between virus-specific IFN-γ-producing cells and protection has been suggested in different studies where different vaccine candidates were tested, although future works should elucidate whether IFN-γ release by specific cell types is related to protection or disease development.


Assuntos
Vírus da Febre Suína Africana , Febre Suína Africana , Suínos , Animais , Citocinas/metabolismo , Interleucina-6/metabolismo , Interleucina-1/metabolismo , Sus scrofa
4.
Cytokine ; 162: 156102, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36476991

RESUMO

INTRODUCTION: Chronic inflammatory or autoimmune diseases are commonly treated with immunosuppressive medication such as NSAIDs, corticosteroids, or antibodies against specific cytokines (TNF, IL-1 IL-17, IL-23, etc.) or signalling cascades (e.g. JAK-STAT inhibitors). Using sequencing data to locate genetic mutations in relevant genes allows the identification of alternative targets in a patient-tailored therapy setting. Interleukin (IL)-37 is an anti-inflammatory cytokine with broad effects on innate and adaptive immune cell function. Dysfunctional IL-37 expression or signalling is linked to various autoinflammatory disorders. The administration of recombinant IL-37 to hyperinflammatory patients that are non-responsive to standard treatment bears the potential to alleviate symptoms. METHODS: In this case study, the (hyper)responsiveness of immune cell subsets was investigated in a single patient with a seronegative autoimmune disorder who carries a heterozygous stop-gain variant in IL37 (IL37 Chr2(GRCh37):g.113670640G > A NM_014439.3:c.51G > A p.(Trp17*)). As the patient has been non-responsive to blockage of TNF or IL-1 by Etanercept or Anakinra, respectively, additional in-vitro experiments were set out to elucidate whether treatment with recombinant IL-37 could normalise observed immune cell functions. FINDINGS: Characterisation of immune cell function showed no elevated overall production of acute-phase pro-inflammatory cytokines by patient PBMCs and neutrophils at baseline or upon stimulation. T-cell responses were elevated, as was the metabolic activity and IL-1Ra production of PBMCs at baseline. The identified stop-gain variant in IL37 does not result in the absence of the protein in circulation. In line with this, treatment with recombinant IL-37 did overall not dampen immune responses with the exception of the complete suppression of IL-17. CONCLUSION: The heterozygous stop-gain variant in IL37 (IL37 NM_014439.3:c.51G > A p.(Trp17*)) is not of functional relevance as we observed no clear pro-inflammatory phenotype in immune cells of a patient carrying this variant.


Assuntos
Interleucina-17 , Interleucina-1 , Humanos , Interleucina-1/metabolismo , Interleucina-17/genética , Citocinas/genética , Inflamação , Expressão Gênica
5.
Biochem Biophys Res Commun ; 642: 97-106, 2023 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-36566568

RESUMO

As in other mammalian tissues, the extracellular matrix (ECM) of skin functions as mechanical support and regulative environment that guides the behavior of the cells. ECM is a gel-like structure that is primarily composed of structural and nonstructural proteins. While the content of structural proteins is stable, the level of nonstructural ECM proteins, such as thrombospondin-4 (THBS4), is dynamically regulated. In a previous work we demonstrated that THBS4 stimulated cutaneous wound healing. In this work we discovered that in addition to proliferation, THBS4 stimulated the migration of primary keratinocytes in 3D. By using a proteotransciptomic approach we found that stimulation of keratinocytes with THBS4 regulated the activity of signaling pathways linked to proliferation, migration, inflammation and differentiation. Interestingly, some of the regulated genes (eg IL37, TSLP) have been associated with the pathogenesis of atopic dermatitis (AD). We concluded that THBS4 is a promising candidate for novel wound healing therapies and suggest that there is a potential convergence of pathways that stimulate cutaneous wound healing with those active in the pathogenesis of inflammatory skin diseases.


Assuntos
Queratinócitos , Pele , Animais , Humanos , Queratinócitos/metabolismo , Pele/metabolismo , Trombospondinas/metabolismo , Inflamação/patologia , Proliferação de Células , Mamíferos , Interleucina-1/metabolismo
6.
Sci Immunol ; 7(78): eade5728, 2022 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-36525507

RESUMO

Interleukin-1 (IL-1) family cytokines are key barrier cytokines that are typically expressed as inactive, or partially active, precursors that require proteolysis within their amino termini for activation. IL-37 is an enigmatic member of the IL-1 family that has been proposed to be activated by caspase-1 and to exert anti-inflammatory activity through engagement of the IL-18R and SIGIRR. However, here we show that the longest IL-37 isoform, IL-37b, exhibits robust proinflammatory activity upon amino-terminal proteolysis by neutrophil elastase or cathepsin S. In sharp contrast, caspase-1 failed to process or activate IL-37 at concentrations that robustly activated its canonical substrate, IL-1ß. IL-37 and IL-36 exhibit high structural homology, and, consistent with this, a K53-truncated form of IL-37, mimicking the cathepsin S-processed form of this cytokine, was found to exert its proinflammatory effects via IL-36 receptor engagement and produced an inflammatory signature practically identical to IL-36. Administration of K53-truncated IL-37b intraperitoneally into wild-type mice also elicited an inflammatory response that was attenuated in IL-36R-/- animals. These data demonstrate that, in common with other IL-1 family members, mature IL-37 can also elicit proinflammatory effects upon processing by specific proteases.


Assuntos
Interleucina-1 , Peptídeo Hidrolases , Receptores de Interleucina , Animais , Camundongos , Caspases , Catepsinas , Citocinas , Interleucina-1/metabolismo , Células Mieloides , Receptores de Interleucina/metabolismo
7.
Nutrients ; 14(23)2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36501011

RESUMO

Collagen-based products are found in different pharmaceuticals, medicine, food, and cosmetics products for a wide variety of applications. However, its use to prevent or improve the health of skin is growing dizzyingly. Therefore, this study investigated whether collagen peptides could induce fibroblast and keratinocyte proliferation and activation beyond reducing an inflammatory response induced by lipopolysaccharide (LPS). Human skin fibroblasts (CCD-1072Sk) and human keratinocytes (hKT-nh-skp-KT0026) were seeded at a concentration of 5 × 104 cells/mL. LPS (10 ng/mL) and three doses of collagen peptides (2.5 mg/mL, 5 mg/mL, 10 mg/mL) were used. The readout parameters were cell proliferation; expression of inducible nitric oxide synthase (iNOS); expression of pro-collagen-1α by fibroblasts; and secretion of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor α (TNF-α), transforming growth factor ß (TGF-ß), and vascular endothelial growth factor (VEGF) by both cell types. The results demonstrated that all doses of collagen supplementation induced increased proliferation of both human fibroblasts (p < 0.01) and human keratinocytes (p < 0.001), while only the dose of 10 mg/mL induced an increased expression of pro-collagen-1α by fibroblasts. Similarly, only the dose of 10 mg/mL reduced LPS-induced iNOS expression in fibroblasts (p < 0.05) and keratinocytes (p < 0.01). In addition, collagen supplementation reduced the LPS-induced IL-1ß (p < 0.05), IL-6 (p < 0.001), IL-8 (p < 0.01), and TNF-α (p < 0.05), and increased the TGF-ß and VEGF expression in fibroblasts. Furthermore, collagen supplementation reduced the LPS-induced IL-1ß (p < 0.01), IL-6 (p < 0.01), IL-8 (p < 0.01), and TNF-α (p < 0.001), and increased the TGF-ß (p < 0.05) and VEGF (p < 0.05) expression in keratinocytes. In conclusion, collagen peptides were found to induce fibroblast and keratinocyte proliferation and pro-collagen-1α expression, involving increased expression of TGF-ß and VEGF, as well as the suppression of an inflammatory response induced by LPS.


Assuntos
Interleucina-8 , Fator de Necrose Tumoral alfa , Humanos , Anti-Inflamatórios/metabolismo , Proliferação de Células , Células Cultivadas , Fibroblastos/metabolismo , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Queratinócitos/metabolismo , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Colágeno/farmacologia
8.
Front Cell Infect Microbiol ; 12: 1040749, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36579341

RESUMO

Background: The effect of chronic psychological stress on hepatitis and liver fibrosis is concerned. However, its mechanism remains unclear. We investigated the effect and mechanism of chronic psychological stress in promoting liver injury and fibrosis through gut. Methods: Sixty male SD rats were randomly assigned to 6 groups. Rat models of chronic psychological stress (4 weeks) and liver fibrosis (8 weeks) were established. The diversity of gut microbiota in intestinal feces, permeability of intestinal mucosa, pathologies of intestinal and liver tissues, collagen fibers, protein expressions of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor kappa ß (NF-κß), tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1) in liver tissue, liver function and coagulation function in blood and lipopolysaccharide (LPS) in portal vein blood were detected and analyzed. Results: The diversities and abundances of gut microbiota were significant differences in rats among each group. The pathological lesions of intestinal and liver tissues, decreased expression of occludin protein in intestinal mucosa, deposition of collagen fibers and increased protein expression of TLR4, MyD88, NF-κß, TNF-α and IL-1 in liver tissue, increased LPS level in portal vein blood, and abnormalities of liver function and coagulation function, were observed in rats exposed to chronic psychological stress or liver fibrosis. There were significant differences with normal rats. When the dual intervention factors of chronic psychological stress and liver fibrosis were superimposed, the above indicators were further aggravated. Conclusion: Chronic psychological stress promotes liver injury and fibrosis, depending on changes in the diversity of gut microbiota and increased intestinal permeability caused by psychological stress, LPS that enters liver and acts on TLR4, and active LPS-TLR4 pathway depend on MyD88. It demonstrates the possibility of existence of brain-gut-liver axis.


Assuntos
Lipopolissacarídeos , Receptor 4 Toll-Like , Ratos , Masculino , Animais , Receptor 4 Toll-Like/metabolismo , Lipopolissacarídeos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Transdução de Sinais , Fator 88 de Diferenciação Mieloide/metabolismo , Ratos Sprague-Dawley , NF-kappa B/metabolismo , Cirrose Hepática , Interleucina-1/metabolismo , Interleucina-1/farmacologia , Colágeno/metabolismo , Encéfalo/metabolismo
9.
Int J Mol Sci ; 23(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36362030

RESUMO

Much evidence suggests autoimmunity in the etiopathogenesis of periodontal disease. In fact, in periodontitis, there is antibody production against collagen, DNA, and IgG, as well as increased IgA expression, T cell dysfunction, high expression of class II MHC molecules on the surface of gingival epithelial cells in inflamed tissues, activation of NK cells, and the generation of antibodies against the azurophil granules of polymorphonuclear leukocytes. In general, direct activation of autoreactive immune cells and production of TNF can activate neutrophils to release pro-inflammatory enzymes with tissue damage in the gingiva. Gingival inflammation and, in the most serious cases, periodontitis, are mainly due to the dysbiosis of the commensal oral microbiota that triggers the immune system. This inflammatory pathological state can affect the periodontal ligament, bone, and the entire gingival tissue. Oral tolerance can be abrogated by some cytokines produced by epithelial cells and activated immune cells, including mast cells (MCs). Periodontal cells and inflammatory-immune cells, including mast cells (MCs), produce cytokines and chemokines, mediating local inflammation of the gingival, along with destruction of the periodontal ligament and alveolar bone. Immune-cell activation and recruitment can be induced by inflammatory cytokines, such as IL-1, TNF, IL-33, and bacterial products, including lipopolysaccharide (LPS). IL-1 and IL-33 are pleiotropic cytokines from members of the IL-1 family, which mediate inflammation of MCs and contribute to many key features of periodontitis and other inflammatory disorders. IL-33 activates several immune cells, including lymphocytes, Th2 cells, and MCs in both innate and acquired immunological diseases. The classic therapies for periodontitis include non-surgical periodontal treatment, surgery, antibiotics, anti-inflammatory drugs, and surgery, which have been only partially effective. Recently, a natural cytokine, IL-37, a member of the IL-1 family and a suppressor of IL-1b, has received considerable attention for the treatment of inflammatory diseases. In this article, we report that IL-37 may be an important and effective therapeutic cytokine that may inhibit periodontal inflammation. The purpose of this paper is to study the relationship between MCs, IL-1, IL-33, and IL-37 inhibition in acute and chronic inflamed gingival tissue.


Assuntos
Gengivite , Interleucina-33 , Mastócitos , Humanos , Citocinas , Gengivite/metabolismo , Gengivite/patologia , Inflamação , Interleucina-33/metabolismo , Mastócitos/metabolismo , Mastócitos/patologia , Periodontite/metabolismo , Periodontite/patologia , Interleucina-1/metabolismo
10.
Biomed Res Int ; 2022: 3865844, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36246974

RESUMO

Matriptases are cell surface proteolytic enzymes belonging to the type II transmembrane serine protease family that mediate inflammatory skin disorders and cancer progression. Matriptases may affect the development of periodontitis via protease-activated receptor-2 activity. However, the cellular mechanism by which matriptases are involved in periodontitis is unknown. In this study, we examined the antiperiodontitis effects of matriptase on Porphyromonas gingivalis-derived lipopolysaccharide (PG-LPS)-stimulated human gingival fibroblasts (HGFs). Matriptase small interfering RNA-transfected HGFs were treated with PG-LPS. The mRNA and protein levels of proinflammatory cytokines and matrix metalloproteinase 1 (MMP-1) were evaluated using the quantitative real-time polymerase chain reaction (qRT-PCR) and an enzyme-linked immunosorbent assay (ELISA), respectively. Western blot analyses were performed to measure the levels of Toll-like receptor 4 (TLR4)/interleukin-1 (IL-1) receptor-associated kinase (IRAK)/transforming growth factor ß-activated kinase 1 (TAK1), p65, and p50 in PG-LPS-stimulated HGFs. Matriptase downregulation inhibited LPS-induced proinflammatory cytokine expression, including the expression of IL-6, IL-8, tumor necrosis factor-α (TNF-α), and IL-Iß. Moreover, matriptase downregulation inhibited PG-LPS-stimulated MMP-1 expression. Additionally, we confirmed that the mechanism underlying the effects of matriptase downregulation involves the suppression of PG-LPS-induced IRAK1/TAK1 and NF-κB. These results suggest that downregulation of matriptase PG-LPS-induced MMP-1 and proinflammatory cytokine expression via TLR4-mediated IRAK1/TAK1 and NF-κB signaling pathways in HGFs.


Assuntos
Fibroblastos , Metaloproteinase 1 da Matriz , Periodontite , Serina Endopeptidases , Citocinas/metabolismo , Regulação para Baixo , Fibroblastos/metabolismo , Humanos , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/toxicidade , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , NF-kappa B/metabolismo , Periodontite/genética , Periodontite/metabolismo , Porphyromonas gingivalis , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores Ativados por Proteinase/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Front Immunol ; 13: 984045, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36268013

RESUMO

IL-1 plays a crucial role in triggering sterile inflammation following tissue injury. Although most studies associate IL-1 release by injured cells to the recruitment of neutrophils for tissue repair, the inflammatory cascade involves several molecular and cellular actors whose role remains to be specified. In the present study, we identified dermal fibroblasts among the IL-1R1-expressing skin cells as key sensors of IL-1 released by injured keratinocytes. After in vitro stimulation by recombinant cytokines or protein extracts of lysed keratinocytes containing high concentrations of IL-1, we show that dermal fibroblasts are by far the most IL-1-responsive cells compared to keratinocytes, melanocytes and endothelial cells. Fibroblasts have the property to respond to very low concentrations of IL-1 (from 10 fg/ml), even in the presence of 100-fold higher concentrations of IL-1RA, by increasing their expression of chemokines such as IL-8 for neutrophil recruitment. The capacity of IL-1-stimulated fibroblasts to attract neutrophils has been demonstrated both in vitro using cell migration assay and in vivo using a model of superficial epidermal lesion in IL-1R1-deficient mice which harbored reduced expression of inflammatory mediators and neutrophil skin infiltration. Together, our results shed a light on dermal fibroblasts as key relay cells in the chain of sterile inflammation induced after epidermal lesion.


Assuntos
Dermatite , Interleucina-1 , Camundongos , Animais , Interleucina-1/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-8/metabolismo , Células Endoteliais/metabolismo , Células Cultivadas , Queratinócitos/metabolismo , Dermatite/metabolismo , Fibroblastos/metabolismo , Inflamação/metabolismo
12.
Vet Res ; 53(1): 87, 2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36273217

RESUMO

Muscle larvae of Trichinella spiralis parasitize the host intestinal epithelium. The mechanisms of exosomes participating in the invasion of T. spiralis muscle larvae are unclear. Hence, the purpose of this study was to explore the effect of exosomes derived from T. spiralis infective larvae (TsExos) on the barrier function of porcine small intestinal epithelial cells (IPEC-J2). First, TsExos were successfully obtained, and their ingestion by epithelial cells was validated. Furthermore, the optimal induction condition was determined by the CCK8 kit, and we found that exposure to 150 µg/mL TsExos for 12/24 h decreased the viability of IPEC-J2 cells by 30%. Based on this outcome, the effects of TsExos on cell biological processes and tight junctions were studied. After coincubation of TsExos and IPEC-J2 cells, the results showed a significant increase in the content of FITC-dextran and in the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS). The rate of apoptosis increased by 12.57%, and nuclear pyknosis and nuclear rupture were observed. After the cells were induced by TsExos, the expression of IL-1 was upregulated, but the expression of IL-10, TGF-ß, TLR-5, MUC-1 and MUC-2 was downregulated. TsExo induction also led to a decrease in the levels of ZO-1, CLDN-3, and OCLN. In conclusion, TsExos are involved in several cellular biological processes, and they function by disrupting physiological and biochemical processes, hyperactivating innate immunity, and damaging tight junctions.


Assuntos
Exossomos , Trichinella spiralis , Suínos , Animais , Trichinella spiralis/fisiologia , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptor 5 Toll-Like/metabolismo , Mucosa Intestinal , Células Epiteliais/metabolismo , Larva/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Lactato Desidrogenases/metabolismo , Interleucina-1/metabolismo
13.
Int J Mol Sci ; 23(19)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36233224

RESUMO

Mesangial cells (MC) maintain the architecture and cellular communication and indirectly join in the glomerular filtration rate for the correct functioning of the glomerulus. Consequently, these cells are activated constantly in response to changes in the intraglomerular environment due to a metabolic imbalance or infection. IL-36, a member of the IL-1 family, is a cytokine that initiates and maintains inflammation in different tissues in acute and chronic pathologies, including the skin, lungs, and intestines. In the kidney, IL-36 has been described in the development of tubulointerstitial lesions, the production of an inflammatory environment, and is associated with metabolic and mesangioproliferative disorders. The participation of IL-36 in functional dysregulation and the consequent generation of the inflammatory environment by MCs in the presence of microbial stimulation is not yet elucidated. In this work, the MES SV40 cell cultures were stimulated with classical pathogen-associated molecular patterns (PAMPs), mimicking an infection by negative and positive bacteria as well as a viral infection. Lipopolysaccharide (LPS), peptidoglycan (PGN) microbial wall components, and a viral mimic poly I:C were used, and the mRNA and protein expression of the IL-36 members were assessed. We observed a differential and dose-dependent IL-36 mRNA and protein expression under LPS, PGN, and poly I:C stimulation. IL-36ß was only found when the cells were treated with LPS, while IL-36α and IL-36γ were favored by PGN and poly I:C stimulation. We suggest that the microbial components participate in the activation of MCs, leading them to the production of IL-36, in which a specific member may participate in the origin and maintenance of inflammation in the glomerular environment that is associated with infections.


Assuntos
Citocinas , Lipopolissacarídeos , Citocinas/metabolismo , Humanos , Inflamação , Interleucina-1/genética , Interleucina-1/metabolismo , Lipopolissacarídeos/farmacologia , Padrões Moleculares Associados a Patógenos , Peptidoglicano/farmacologia , Poli I-C , RNA Mensageiro/genética
14.
Cells ; 11(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36291105

RESUMO

Interleukin-33 (IL-33), a member of the IL-1 cytokine family and a multifunctional cytokine, plays critical roles in maintaining host homeostasis and in pathological conditions, such as allergy, infectious diseases, and cancer, by acting on multiple types of immune cells and promoting type 1 and 2 immune responses. IL-33 is rapidly released by immune and non-immune cells upon stimulation by stress, acting as an "alarmin" by binding to its receptor, suppression of tumorigenicity 2 (ST2), to trigger downstream signaling pathways and activate inflammatory and immune responses. It has been recognized that IL-33 displays dual-functioning immune regulatory effects in many diseases and has both pro- and anti-tumorigenic effects, likely depending on its primary target cells, IL-33/sST2 expression levels, cellular context, and the cytokine microenvironment. Herein, we summarize our current understanding of the biological functions of IL-33 and its roles in the pathogenesis of various conditions, including inflammatory and autoimmune diseases, infections, cancers, and cases of organ transplantation. We emphasize the nature of context-dependent dual immune regulatory functions of IL-33 in many cells and diseases and review systemic studies to understand the distinct roles of IL-33 in different cells, which is essential to the development of more effective diagnoses and therapeutic approaches for IL-33-related diseases.


Assuntos
Doenças Autoimunes , Infecções , Inflamação , Interleucina-1 , Interleucina-33 , Neoplasias , Humanos , Doenças Autoimunes/imunologia , Interleucina-1/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Neoplasias/imunologia , Microambiente Tumoral , Inflamação/imunologia , Transplante de Órgãos , Infecções/imunologia
15.
Eur Cytokine Netw ; 33(2): 19-29, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36266987

RESUMO

IL-36γ, a pro-inflammatory member of the IL-1 cytokine superfamily, can be induced and secreted by normal human foreskin keratinocytes (HFKs) in response to pathogenic stimuli, however, the mechanisms underlying the secretion are unknown. In this study, we demonstrate that stimulation with the TLR3 agonist, poly (I:C), led to a delayed secretion of IL-36γ compared to stimulation with the TLR5 agonist, flagellin, despite equal levels of the cytokine (p = 0.006). IL-36γ was shown to be released from HFKs in its inactive, uncleaved form, based on western blotting. Moreover, recombinant IL-36γ in its activated, cleaved form induced endogenous IL-36γ 10-fold (p = 0.004) and CXCL8 five-fold (p = 0.003) over baseline levels compared to unactivated full-length recombinant IL-36γ. The ratio of LC3b-II/LC3b-I was significantly higher in poly(I:C)-treated cells compared to flagellin-treated and unstimulated controls without a change in SQSTM1/p62 after 24 hours of stimulation (p = 0.043). Under fluorescence microscopy, poly(I:C) led to a two-fold increase at eight hours and four-fold increase at 24 hours in accumulated autophagosomes post-stimulation (p = 0.032). In contrast, autophagosomes were unchanged relative to baseline in response to flagellin. Bafilomycin A1 treatment enhanced poly(I:C)-mediated IL-36γ secretion (p = 0.044) while rapamycin led to a noticeable, but non-significant, increase in flagellin-mediated IL-36γ secretion, indicating that interrupting autophagic flux can alter IL-3γ grelease from HFKs. Finally, we show that, compared to clinically normal laryngeal tissue, there were significantly higher levels of LC3b-II in HPV-infected respiratory papilloma tissue, indicating a higher number of autophagosomes; a signature of disrupted autophagic flux.


Assuntos
Flagelina , Interleucina-1 , Humanos , Flagelina/farmacologia , Interleucina-1/farmacologia , Interleucina-1/metabolismo , Receptor 3 Toll-Like/metabolismo , Receptor 5 Toll-Like , Proteína Sequestossoma-1 , Queratinócitos/metabolismo , Poli I-C/farmacologia , Citocinas , Autofagia , Sirolimo/farmacologia
16.
J Wound Care ; 31(10): 872-881, 2022 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-36240793

RESUMO

OBJECTIVE: Alcohol consumption combined with ageing alters the healing process of the skin. We evaluated whether ageing decreases the healing of incisional wounds in the skin of Wistar rats of Universidade de Chile of variety B (UChB). METHOD: A total of 20 adult rats and 20 older UChB rats, divided into two groups which underwent surgical aggression in the anterior region of the abdomen, were used: G1, adult rats (100 days old, control) with water and 10% ethanol; G2, aged rats (540 days old, experimental) with water and 10% ethanol; evaluated at 4, 7, 14 and 21 days after surgery. RESULTS: Ageing did not alter the rupture force and collagen elasticity and resistance. There were increases in telomerase with the implementation of cellular senescence, in interleukin 1-alpha (IL-1α) at 14 days of healing, in epidermal growth factor (EGF) at 14 and 21 days of healing with delayed growth and development of keratinocytes, also an increase of IL-ß at 4 days, and decrease in tumour necrosis factor (TNFα) at 7 days, associated with chronic scarring. There was an increase in vascular endothelial growth factor (VEGF) at 4 and 7 days, responsible for the early vessels re-establishment. There was a decrease in transforming growth factor 2-beta (TGFß2) and ß3 at 4 and 7 days of healing respectively, and estradiol at 4 days. CONCLUSION: Ageing decreases the skin healing in incisional wounds in alcohol-preferring rats.


Assuntos
Telomerase , Fator A de Crescimento do Endotélio Vascular , Envelhecimento , Animais , Colágeno/metabolismo , Fator de Crescimento Epidérmico , Estradiol/metabolismo , Etanol/metabolismo , Interleucina-1/metabolismo , Ratos , Ratos Wistar , Pele/lesões , Telomerase/metabolismo , Fator de Crescimento Transformador beta , Fatores de Crescimento Transformadores/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo , Água/metabolismo
17.
Virology ; 576: 134-140, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36244319

RESUMO

Gammaherpesviruses establish life-long infection in over 95% of adults and are associated with several cancers, including B cell lymphomas. Using the murine gammaherpesvirus 68 (MHV68) animal model, we previously showed a pro-viral role of Interleukin-1 (IL-1) signaling that supported viral reactivation during the establishment of chronic infection. Unexpectedly, in this study we found that the proviral effects of IL-1 signaling originally observed during the establishment of chronic gammaherpesvirus infection convert to antiviral effects during the long-term stage of infection. Specifically, IL-1 signaling promoted expansion of antiviral CD8+ T cells and control of viral reactivation in the peritoneal cavity of a long-term infected host. Using a novel mouse model of T cell-specific IL-1 signaling deficiency, we found that the antiviral effects of IL-1 signaling were T cell extrinsic. Our study highlights a dynamic nature of host factors that shape the parameters of chronic gammaherpesvirus infection.


Assuntos
Gammaherpesvirinae , Infecções por Herpesviridae , Interleucina-1 , Animais , Camundongos , Antivirais , Linfócitos B , Linfócitos T CD8-Positivos/patologia , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/metabolismo , Interleucina-1/imunologia , Interleucina-1/metabolismo , Camundongos Endogâmicos C57BL , Latência Viral
18.
EMBO Rep ; 23(11): e54603, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36161689

RESUMO

Aberrant activation of inflammation signaling triggered by tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), and interleukin-17 (IL-17) is associated with immunopathology. Here, we identify neural precursor cells expressed developmentally down-regulated gene 4-like (NEDD4L), a HECT type E3 ligase, as a common negative regulator of signaling induced by TNF-α, IL-1, and IL-17. NEDD4L modulates the degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2) via constitutively and directly binding to MEKK2 and promotes its poly-ubiquitination. In interleukin-17 receptor (IL-17R) signaling, Nedd4l knockdown or deficiency enhances IL-17-induced p38 and NF-κB activation and the production of proinflammatory cytokines and chemokines in a MEKK2-dependent manner. We further show that IL-17-induced MEKK2 Ser520 phosphorylation is required not only for downstream p38 and NF-κB activation but also for NEDD4L-mediated MEKK2 degradation and the subsequent shutdown of IL-17R signaling. Importantly, Nedd4l-deficient mice show increased susceptibility to IL-17-induced inflammation and aggravated symptoms of experimental autoimmune encephalomyelitis (EAE) in IL-17R signaling-dependent manner. These data suggest that NEDD4L acts as an inhibitor of IL-17R signaling, which ameliorates the pathogenesis of IL-17-mediated autoimmune diseases.


Assuntos
Encefalomielite Autoimune Experimental , MAP Quinase Quinase Quinase 2 , Ubiquitina-Proteína Ligases Nedd4 , Células-Tronco Neurais , Animais , Camundongos , Encefalomielite Autoimune Experimental/genética , Inflamação/metabolismo , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-17/genética , Células-Tronco Neurais/metabolismo , NF-kappa B/metabolismo , Fosforilação , Fator de Necrose Tumoral alfa/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitinação , Ubiquitina-Proteína Ligases Nedd4/metabolismo , MAP Quinase Quinase Quinase 2/metabolismo
19.
Biomolecules ; 12(9)2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-36139066

RESUMO

Diabetes mellitus (DM) is one of the most debilitating chronic diseases worldwide, with increased prevalence and incidence. In addition to its macrovascular damage, through its microvascular complications, such as Diabetic Kidney Disease (DKD), DM further compounds the quality of life of these patients. Considering DKD is the main cause of end-stage renal disease (ESRD) in developed countries, extensive research is currently investigating the matrix of DKD pathophysiology. Hyperglycemia, inflammation and oxidative stress (OS) are the main mechanisms behind this disease. By generating pro-inflammatory factors (e.g., IL-1,6,18, TNF-α, TGF-ß, NF-κB, MCP-1, VCAM-1, ICAM-1) and the activation of diverse pathways (e.g., PKC, ROCK, AGE/RAGE, JAK-STAT), they promote a pro-oxidant state with impairment of the antioxidant system (NRF2/KEAP1/ARE pathway) and, finally, alterations in the renal filtration unit. Hitherto, a wide spectrum of pre-clinical and clinical studies shows the beneficial use of NRF2-inducing strategies, such as NRF2 activators (e.g., Bardoxolone methyl, Curcumin, Sulforaphane and their analogues), and other natural compounds with antioxidant properties in DKD treatment. However, limitations regarding the lack of larger clinical trials, solubility or delivery hamper their implementation for clinical use. Therefore, in this review, we will discuss DKD mechanisms, especially oxidative stress (OS) and NRF2/KEAP1/ARE involvement, while highlighting the potential of therapeutic approaches that target DKD via OS.


Assuntos
Curcumina , Nefropatias Diabéticas , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Curcumina/uso terapêutico , Nefropatias Diabéticas/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Ácido Oleanólico/análogos & derivados , Estresse Oxidativo , Qualidade de Vida , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
20.
Nutrients ; 14(18)2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36145086

RESUMO

Ulcerative colitis (UC) patients often avoid foods containing fermentable fibers as some can promote symptoms during active disease. Pectin has been identified as a more protective fermentable fiber, but little has been done to determine the interaction between pectin and bioactive compounds present in foods containing that fiber type. Quercetin and chlorogenic acid, two bioactives in stone fruits, may have anti-cancer, anti-oxidant, and anti-inflammatory properties. We hypothesized that quercetin and chlorogenic acid, in the presence of the fermentable fiber pectin, may suppress the expression of pro-inflammatory molecules, alter the luminal environment, and alter colonocyte proliferation, thereby protecting against recurring bouts of UC. Rats (n = 63) received one of three purified diets (control, 0.45% quercetin, 0.05% chlorogenic acid) containing 6% pectin for 3 weeks before exposure to dextran sodium sulfate (DSS, 3% for 48 h, 3x, 2 wk separation, n = 11/diet) in drinking water to initiate UC, or control (no DSS, n = 10/diet) treatments prior to termination at 9 weeks. DSS increased the fecal moisture content (p < 0.05) and SCFA concentrations (acetate, p < 0.05; butyrate, p < 0.05). Quercetin and chlorogenic acid diets maintained SLC5A8 (SCFA transporter) mRNA levels in DSS-treated rats at levels similar to those not exposed to DSS. DSS increased injury (p < 0.0001) and inflammation (p < 0.01) scores, with no differences noted due to diet. Compared to the control diet, chlorogenic acid decreased NF-κB activity in DSS-treated rats (p < 0.05). Quercetin and chlorogenic acid may contribute to the healthy regulation of NF-κB activation (via mRNA expression of IκΒα, Tollip, and IL-1). Quercetin enhanced injury-repair molecule FGF-2 expression (p < 0.01), but neither diet nor DSS treatment altered proliferation. Although quercetin and chlorogenic acid did not protect against overt indicators of injury and inflammation, or fecal SCFA concentrations, compared to the control diet, their influence on the expression of injury repair molecules, pro-inflammatory cytokines, SCFA transport proteins, and NF-κB inhibitory molecules suggests beneficial influences on major pathways involved in DSS-induced UC. Therefore, in healthy individuals or during periods of remission, quercetin and chlorogenic acid may promote a healthier colon, and may suppress some of the signaling involved in inflammation promotion during active disease.


Assuntos
Colite Ulcerativa , Colite , Água Potável , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Butiratos/metabolismo , Proteínas de Transporte/metabolismo , Ácido Clorogênico/metabolismo , Colite/induzido quimicamente , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/prevenção & controle , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana , Dieta , Fibras na Dieta/metabolismo , Modelos Animais de Doenças , Água Potável/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Inflamação/metabolismo , Interleucina-1/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , NF-kappa B/genética , NF-kappa B/metabolismo , Pectinas/metabolismo , Pectinas/farmacologia , Quercetina/metabolismo , Quercetina/farmacologia , RNA Mensageiro/metabolismo , Ratos
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