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1.
Sci Rep ; 13(1): 1827, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36726024

RESUMO

Type I interferons (IFN-Is) have been harnessed for cancer therapies due to their immunostimulatory functions. However, certain tumor-tolerating activities by IFN-Is also exist, and may potentially thwart their therapeutic effects. In this respect, our previous studies have demonstrated a monocyte-orchestrated, IFN-I-to-IL-4 cytokine axis, which can subsequently drive M2-skewed pro-tumoral polarization of macrophages. Whether other IFN-dependent signals may also contribute to such an unconventional circumstance of M2-like macrophage skewing remain unexplored. Herein, we first unveil IL-6 as another ligand that participates in IFN-dependent induction of a typical M2 marker (ARG1) in transitional monocytes. Indeed, IL-6 significantly promotes IL-4-dependent induction of a major group of prominent M2 markers in mouse bone marrow-derived macrophages (BMDMs) and human peripheral blood-derived macrophages, while it alone does not engage marked increases of these markers. Such a pattern of regulation is confirmed globally by RNAseq analyses in BMDMs, which in turn suggests an association of IL-6-amplified subset of M2 genes with the ERK1/2 signaling pathway. Interestingly, pharmacological experiments establish the role of SHP2-ERK cascade in mediating IL-6's enhancement effect on these M2 targets. Similar approaches also validate the involvement of IL-6/ERK signaling in promoting the IFN-dependent, unconventional M2-skewing phenotype in transitional monocytes. Furthermore, an inhibitor of ERK signaling cooperates with an IFN-I inducer to enable a greater antitumor effect, which correlates with suppression of treatment-elicited ARG1. The present work establishes a role of IL-6/ERK signaling in promoting M2-like macrophage polarization, and suggests this axis as a potential therapeutic target for combination with IFN-I-based cancer treatments.


Assuntos
Interferon Tipo I , Neoplasias , Camundongos , Animais , Humanos , Interleucina-6/metabolismo , Interleucina-4/metabolismo , Macrófagos/metabolismo , Transdução de Sinais , Neoplasias/metabolismo , Interferon Tipo I/metabolismo
2.
Acta Vet Scand ; 65(1): 2, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36703227

RESUMO

BACKGROUND: Canine leishmaniosis (CanL) is a systemic disease caused by the protozoan parasite Leishmania infantum with a wide spectrum of clinical signs, with cutaneous, ocular, renal and lymphoreactive conditions prevailing in the clinical setting. The immune system plays a pivotal role in the evolution of Leishmania infection and its response to antileishmanial treatment. Cytokines are important immune response mediators that are released by activated lymphocytes and less so by other immunocytes. In dogs with leishmaniosis, IFN-γ and IL-4 have been recognized as the main activators of cellular and humoral immunity, respectively. The objective of this study was to investigate intracellular IL-4 and IFN-γ expression by CD4 + and CD8 + lymphocytes in the peripheral blood of symptomatic dogs before and after combined antileishmanial treatment with miltefosine and allopurinol. RESULTS: Postantileishmanial treatment CD4 + IL-4 + and CD8 + IL-4 + cell counts were significantly decreased, although no similar changes were observed in the comparisons made between the pre- and posttreatment CD4 + IFN-γ + and CD8 + IFN-γ + counts and ratios. CONCLUSION: The findings indicate that IL-4 production by T cells may facilitate the symptomatic phase of CanL, whereas IFN-γ production by CD4 + and CD8 + cells may indicate its negligible role in the evolution of natural CanL and perhaps the equivocal positive influence of antileishmanial treatment.


Assuntos
Doenças do Cão , Leishmania infantum , Leishmaniose Visceral , Animais , Cães , Interleucina-4 , Estudos Transversais , Alopurinol/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/veterinária , Interferon gama , Linfócitos T CD8-Positivos
3.
Skin Res Technol ; 29(1): e13255, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36704886

RESUMO

OBJECTIVE: To study the expression of interleukin-1ß (IL-1ß), interleukin-4 (IL-4), interferon-γ (IFN-γ) and tumour necrosis factor α (TNF-α) in different tissue in a dinitrochlorobenzene (DNCB)-induced ear swelling test in mice and further evaluate the correlation between the cytokine expression in different tissues and the degree of ear swelling. METHODS: The mice were sensitised with a 0.50% DNCB solution on their back for 3 days. After 7 days, the thickness of their ears was measured and grouped. Different concentrations of the DNCB solution were challenged in the left ear of each group of mice, and the right ear was used as the control. The thickness of both ears was measured every 24 h, and the mice were sacrificed 72 h after the challenge. The expressions of IL-1ß, IL-4, IFN-γ and TNF-α in the mouse serum, lymph node and ear tissue were quantified by enzyme-linked immunosorbent assay, respectively. RESULTS: There was a linear positive correlation between the swelling index of the mouse lateral ear and the challenge concentration of DNCB (r = 0.96, p < 0.01). The high expression of IL-1ß and IL-4 in the lateral ear tissue of the mice was positively correlated with the ear swelling index 48 h after the challenge. The correlation coefficient was 0.78 (p < 0.01). Furthermore, IFN-γ and TNF-α had no significant correlation with the ear swelling index 48 h after the challenge. CONCLUSION: There is a correlation between the degree of ear swelling in mice and the concentration of DNCB and the expression of IL-1ß and IL-4 in the lateral ear tissue. There is a sub-clinical skin sensitivity state in contact allergy.


Assuntos
Dinitroclorobenzeno , Fator de Necrose Tumoral alfa , Camundongos , Animais , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Dinitroclorobenzeno/toxicidade , Interferon gama/metabolismo , Interleucina-4 , Interleucina-1beta , Citocinas/metabolismo
4.
Phytomedicine ; 109: 154559, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36610151

RESUMO

BACKGROUND: Tumor-associated macrophages (TAMs) are important constituent parts of tumor microenvironment that connected with tumor metastasis in melanoma. Connexin 43 (Cx43) was expressed in all the immune cells which modulated different aspects of immune response. However, the concrete molecular mechanism maintains unclear. PURPOSE: The study aimed to find a natural drug monomer effectively reversed the polarity of tumor-associated macrophages inhibiting melanoma metastasis and improving survival time. METHODS: Flow cytometry was used to determine the effects of dioscin on the macrophage phenotype. Western bolt and ELISA were performed to explore the underlying mechanism of dioscin and a co-culture experiment in vitro was applied to assess the role of dioscin on TAMs-mediated melanoma proliferation, invasion and migration. Moreover, in vivo melanoma metastasis models were established for examining effects of dioscin on TAMs-mediated melanoma metastasis. RESULTS: Dioscin repolarized macrophages from M2 towards M1-like phenotype. Dioscin suppressed M2-like phenotype macrophages through enhanced the expression and transport function of Cx43. Furthermore, the stimulation IFN-γ/STAT1 pathway and suppression IL-4/JAK2/STAT3 pathway were major mechanism of dioscin. Importantly, dioscin suppressed Cx43G21R mutation TAMs induced proliferation, invasion, migration and metastasis of melanoma cells. It worthily noting that dioscin ameliorated tumor-associated-macrophages-mediated melanoma metastasis in vitro and vivo. CONCLUSION: Dioscin re-polarized macrophages from M2 to M1 phenotype through activation of Cx43-gap-junction-intercellular-communications (Cx43-GJs)/IFN-γ/STAT1 pathway and inhibition of Cx43-GJs/IL-4/JAK2/STAT3 suppressing migration, invasion and metastasis of melanoma, which provided a theoretical and experimental basis for treating melanoma metastasis.


Assuntos
Conexina 43 , Melanoma , Humanos , Conexina 43/metabolismo , Macrófagos Associados a Tumor/metabolismo , Interleucina-4/metabolismo , Macrófagos , Melanoma/patologia , Linhagem Celular Tumoral , Microambiente Tumoral
5.
BMC Neurol ; 23(1): 7, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609211

RESUMO

BACKGROUND: Cytokine levels have been measured in acute encephalopathy (AE) to determine its pathology or as a diagnostic biomarker to distinguish it from febrile seizures (FS); however, the dynamics of cytokine level changes have not yet been fully captured in these two neurological manifestations. Thus, we aimed to explore the time course of serum cytokine level changes within 72 h after onset in AE and FS. METHODS: We retrospectively measured cytokine level in residual serum samples at multiple timepoints in seven children whose final diagnoses were AE or FS. RESULTS: The levels of 13 cytokines appeared to increase immediately after onset and peaked within 12-24 h after onset: interleukin (IL)-1ß, IL-4 IL-5, IL-6, IL-8, IL-10, IL-17, eotaxin, fibroblast growth factor, granulocyte colony-stimulating factor, interferon gamma, interferon-inducible protein-10, and macrophage chemoattractant protein-1. There were no dynamic changes in the levels of three cytokines (IL-1 receptor agonist, macrophage inflammatory protein-1α, and platelet-derived growth factor-bb) 72 h after onset. Levels of some cytokines decreased to around control levels within 48 h after onset: IL-1ß, IL-4, IL-5, IL-17, fibroblast growth factor, and interferon gamma. The levels of most cytokines appeared to be higher in AE, especially in hemorrhagic shock encephalopathy syndrome, than in FS. CONCLUSIONS: Cytokine levels in both AE and FS change dynamically, such as the levels of several cytokines increased within a few hours after onset and decreased at 12-24 h after onset. Therefore, it will be desirable to make clinical decisions regarding the administration of anti-inflammatory therapy in 24 h after onset in AE.


Assuntos
Encefalopatias , Convulsões Febris , Criança , Humanos , Citocinas , Interleucina-17 , Interferon gama , Interleucina-4 , Estudos Retrospectivos , Interleucina-5
6.
Arthritis Res Ther ; 25(1): 12, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36698198

RESUMO

BACKGROUND: Systemic sclerosis is a rheumatoid disease best known for its fibrotic skin manifestations called scleroderma. Alternatively activated (M2-type) macrophages are normally involved in the resolution of inflammation and wound healing but also in fibrosing diseases such as scleroderma. TRPA1 is a non-selective cation channel, activation of which causes pain and neurogenic inflammation. In the present study, we investigated the role of TRPA1 in bleomycin-induced skin fibrosis mimicking scleroderma. METHODS: Wild type and TRPA1-deficient mice were challenged with intradermal bleomycin injections to induce a scleroderma-mimicking disease. Macrophages were investigated in vitro to evaluate the underlying mechanisms. RESULTS: Bleomycin induced dermal thickening and collagen accumulation in wild type mice and that was significantly attenuated in TRPA1-deficient animals. Accordingly, the expression of collagens 1A1, 1A2, and 3A1 as well as pro-fibrotic factors TGF-beta, CTGF, fibronectin-1 and YKL-40, and M2 macrophage markers Arg1 and MRC1 were lower in TRPA1-deficient than wild type mice. Furthermore, bleomycin was discovered to significantly enhance M2-marker expression particularly in the presence of IL-4 in wild type macrophages in vitro, but not in macrophages harvested from TRPA1-deficient mice. IL-4-induced PPARγ-expression in macrophages was increased by bleomycin, providing a possible mechanism behind the phenomenon. CONCLUSIONS: In conclusion, the results indicate that interfering TRPA1 attenuates fibrotic and inflammatory responses in bleomycin-induced scleroderma. Therefore, TRPA1-blocking treatment could potentially alleviate M2 macrophage driven diseases like systemic sclerosis and scleroderma.


Assuntos
Esclerodermia Localizada , Escleroderma Sistêmico , Camundongos , Animais , Bleomicina/toxicidade , Ativação de Macrófagos , Interleucina-4/efeitos adversos , Interleucina-4/metabolismo , Escleroderma Sistêmico/patologia , Fibrose , Colágeno/metabolismo , Esclerodermia Localizada/induzido quimicamente , Esclerodermia Localizada/patologia , Modelos Animais de Doenças , Pele/patologia , Canal de Cátion TRPA1/genética
7.
PLoS One ; 18(1): e0279893, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36598904

RESUMO

Arsenic is a potent environmental toxicant and human carcinogen. Skin lesions are the most common manifestations of chronic exposure to arsenic. Advanced-stage skin lesions, particularly hyperkeratosis have been recognized as precancerous diseases. However, the underlying mechanism of arsenic-induced skin lesions remains unknown. Periostin, a matricellular protein, is implicated in the pathogenesis of many forms of skin lesions. The objective of this study was to examine whether periostin is associated with arsenic-induced skin lesions. A total of 442 individuals from low- (n = 123) and high-arsenic exposure areas (n = 319) in rural Bangladesh were evaluated for the presence of arsenic-induced skin lesions (Yes/No). Participants with skin lesions were further categorized into two groups: early-stage skin lesions (melanosis and keratosis) and advanced-stage skin lesions (hyperkeratosis). Drinking water, hair, and nail arsenic concentrations were considered as the participants' exposure levels. The higher levels of arsenic and serum periostin were significantly associated with skin lesions. Causal mediation analysis revealed the significant effect of arsenic on skin lesions through the mediator, periostin, suggesting that periostin contributes to the development of skin lesions. When skin lesion was used as a three-category outcome (none, early-stage, and advanced-stage skin lesions), higher serum periostin levels were significantly associated with both early-stage and advanced-stage skin lesions. Median (IQR) periostin levels were progressively increased with the increasing severity of skin lesions. Furthermore, there were general trends in increasing serum type 2 cytokines (IL-4, IL-5, IL-13, and eotaxin) and immunoglobulin E (IgE) levels with the progression of the disease. The median (IQR) of IL-4, IL-5, IL-13, eotaxin, and IgE levels were significantly higher in the early-and advanced-stage skin lesions compared to the group of participants without skin lesions. The results of this study suggest that periostin is implicated in the pathogenesis and progression of arsenic-induced skin lesions through the dysregulation of type 2 immune response.


Assuntos
Arsênio , Ceratose Actínica , Dermatopatias , Humanos , Arsênio/toxicidade , Arsênio/análise , Interleucina-13 , Interleucina-4 , Interleucina-5 , Exposição Ambiental , Abastecimento de Água , Dermatopatias/induzido quimicamente , Imunoglobulina E/efeitos adversos
8.
Eur J Med Res ; 28(1): 7, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36600245

RESUMO

BACKGROUND: Immune indicators are routinely used for the detection of myelodysplastic syndrome (MDS), but these are not utilized as a reference indicator to assess prognosis in MDS-related prognostic evaluation systems, such as the World Health Organizational prognostic scoring system, the international prostate symptom score, and the revised international prostate symptom score. METHODS: We examined immune indicators, including cluster of differentiation (CD)3, CD4, CD8, CD56, CD19, interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-a, and interferon-γ in 155 newly diagnosed MDS patients. We also conducted a correlation analysis with clinical indices. RESULTS: IL-4 was found to be a predictor of survival in these 155 patients using the receiver operating characteristic curve, with 5.155 as the cut-off point. Patients with serum IL-4 levels ≥ 5.155 had a lower overall survival (OS) than those with IL-45.155 at diagnosis. Furthermore, multivariate analysis revealed that IL-4 levels > 5.155 were an independent predictor of OS (hazard ratio: 0.237; 95% confidence interval, 0.114-0.779; P = 0.013). In addition, serum IL-4 expression in the three different scoring systems showed significant differences in the survival of medium- to high-risk MDS patients (P = 0.014, P < 0.001, P < 0.001). CONCLUSIONS: According to our study, IL-4 levels at the time of diagnosis can predict MDS prognosis in patients as a simple index reflecting host systemic immunity.


Assuntos
Interleucina-4 , Síndromes Mielodisplásicas , Masculino , Humanos , Prognóstico , Modelos de Riscos Proporcionais , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Fator de Necrose Tumoral alfa
9.
Cell Transplant ; 32: 9636897221145682, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593749

RESUMO

We aimed to explore whether the effect of progesterone on preeclampsia via the PI3K/AKT signaling pathway. First, we studied the role of progesterone in preeclampsia patients and HTR-8/Svneo cells by adding progesterone. Then PI3K inhibitor LY294002 was added. The effects of progesterone on preeclampsia were also studied in animals by constructing a preeclampsia rat model. CCK-8 and Transwell assay were applied to measure cell viability and invasion ability. ELISA was performed to measure progesterone, MMP-2, MMP-9, pro-inflammatory factors TNF-α, IL-1ß, and anti-inflammatory factors IL-4, IL-10, and IL-13 levels. HE staining was used to detect the pathological changes in uterine spiral artery. Western blot was performed to detect Cyclin D1, PCNA, MMP-2, MMP-9, inflammatory factors TNF-α, IL-1ß, IL-4, IL-10, IL-13, and PI3K/AKT signaling pathway related proteins AKT, p-AKT, PI3K, and p-PI3K expressions. Progesterone could reduce blood pressure and urine protein in pregnant women with preeclampsia. TNF-α and IL-1ß levels were decreased, but IL-4, IL-10, IL-13, cyclin D1, and PCNA levels were increased in pregnant women with preeclampsia after using progesterone. After the use of progesterone, the symptoms of the PE model group were improved. Among them, the lumen of the placental uterine spiral artery was enlarged, and the fibrinoid necrosis of the uterine wall and acute atherosclerotic lesions were relieved. In addition, progesterone promoted HTR-8/Svneo cells proliferation and invasion. However, high expression of MMP-2, MMP-9, p-AKT, and p-PI3K in Normal and preeclampsia groups caused by progesterone was weakened after adding LY294002, indicating that progesterone could activate PI3K/AKT signaling pathway to regulate HTR-8/Svneo cells. Progesterone decreased urine protein and blood pressure of preeclampsia rats in a concentration-dependent manner. Moreover, progesterone activated the PI3K/AKT signaling pathway and inhibited the inflammatory response in preeclampsia rats.


Assuntos
Pré-Eclâmpsia , Trofoblastos , Feminino , Gravidez , Humanos , Ratos , Animais , Trofoblastos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Progesterona/farmacologia , Placenta/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Ciclina D1/metabolismo , Interleucina-10/metabolismo , Pré-Eclâmpsia/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Transdução de Sinais/fisiologia , Movimento Celular
10.
Trop Anim Health Prod ; 55(1): 34, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609787

RESUMO

Gastrointestinal nematode (GINs) infections are one of the causative agents of health and economic issues in sheep production systems worldwide. Considerable genetic variations in resistance or susceptibility in different sheep breeds are documented, but published results are conflicting. Recent advances obtained by high-throughput technologies such as commercial SNP chips, whole-genome sequencing, or whole transcriptome profiling provide new insights into breeding for host resistance or nematode control at the genetic levels. This study aimed to identify potential biomarkers associated with the resistance to ovine GINs through a network analysis approach. Comprehensive gene and protein interaction networks were reconstructed for candidate genes involved in the most related immune pathways associated with resistance to ovine GINs using data mining from literature. Generally, 30 genes including CD53, CHIA, RELN, HRH1, EPS15, LRP8, ATP2B1, IL4, IL5, IL13, IL2RA, IL23R, TNFα, IFNγ, TBX21, SH3RF1, HERC2, PTPN1, BIN1, HERC5, C3AR1, NOS2, STAT5B, STAT4, CCL1, CCL8, VIL1, CXCR1, CXCR2, and CXCR4 located on chromosomes 1, 2, 3, 4, 5, 6, 11, 13, 19, and 20 have been found as containing effective regions with the most related pathways to nematode infections. The results obtained by network analysis showed two functional modules, belonging to the interleukins family (IL4, IL5, IL13, IL23R, and IL2RA) and chemokine receptors or ligands family (CXCR1, CXCR2, CXCR4, CCL1, and CCL8). Interleukins are a group of cytokines that are expressed by white blood cells with a major role in the immune system. Chemokines are also a family of chemoattractant cytokines which play a vital role in cell migration that influence the immune system by a process known as chemotaxis. The results provide useful information for the functional annotation of candidate genes related to parasite resistance and add new information towards a consensus on quantitative trait loci (QTLs) related to the incidence of nematode infections.


Assuntos
Gastroenteropatias , Nematoides , Infecções por Nematoides , Doenças dos Ovinos , Animais , Ovinos/genética , Interleucina-13 , Interleucina-4 , Interleucina-5 , Resistência à Doença/genética , Nematoides/genética , Infecções por Nematoides/genética , Infecções por Nematoides/veterinária , Gastroenteropatias/veterinária , Doenças dos Ovinos/parasitologia
11.
Cell Commun Signal ; 21(1): 18, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36691020

RESUMO

Resistin-like molecules (RELMs) are highly cysteine-rich proteins, including RELMα, RELMß, Resistin, and RELMγ. However, RELMs exhibit significant differences in structure, distribution, and function. The expression of RELMs is regulated by various signaling molecules, such as IL-4, IL-13, and their receptors. In addition, RELMs can mediate numerous signaling pathways, including HMGB1/RAGE, IL-4/IL-4Rα, PI3K/Akt/mTOR signaling pathways, and so on. RELMs proteins are involved in wide range of physiological and pathological processes, including inflammatory response, cell proliferation, glucose metabolism, barrier defense, etc., and participate in the progression of numerous diseases such as lung diseases, intestinal diseases, cardiovascular diseases, and cancers. Meanwhile, RELMs can serve as biomarkers, risk predictors, and therapeutic targets for these diseases. An in-depth understanding of the role of RELMs may provide novel targets or strategies for the treatment and prevention of related diseases. Video abstract.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Pneumopatias , Humanos , Resistina/fisiologia , Interleucina-4 , Fosfatidilinositol 3-Quinases
12.
Biomed Res Int ; 2023: 5124034, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36660452

RESUMO

Background: Galactose-deficient IgA1 (Gd-IgA1) is a critical initiating factor in the pathogenesis of IgA nephropathy (IgAN), which plays an important role in the diagnosis and evaluation of this disease. Moreover, the whole pathogenesis process has an intimate association with the immune response of T and B lymphocytes and their inflammatory factors. There is no specific therapy for IgAN at present. Yiqi Yangyin Formula can significantly reduce urinary protein and hematuria in patients with IgAN. Yiqi Yangying Heluo Formula (YYHF) is optimized on the basis of the above prescription, but its specific mechanism remains to be further studied. Methods: The effect of YYHF on urinary protein and urinary red blood cell count in patients with IgAN was observed by a self-controlled clinical study before and after treatment. On this basis, flow cytometry was used to detect the proportion of T lymphocyte subsets in peripheral blood of patients with IgAN before and after treatment and healthy controls. Meanwhile, the levels of Gd-IgA1, B cell activation factor (BAFF), and their cytokines (IL-4, IL-6, and IL-17) in peripheral blood were detected by enzyme-linked immunosorbent assay. The changes in mechanism-related indicators of the two groups were observed and subject to correlation analysis. Results: (1) Compared with the levels before treatment, 24-hour urinary protein content decreased by 47.7% and urinary red blood cell number decreased by 67% in patients with IgAN intervened by YYHF after 48 weeks of follow-up. (2) Compared with the healthy control group, patients with IgAN showed a significantly increased proportion of Th1 cells, Th17 cells, Th1/Th2, Th1/Treg, Th2/Treg, and Th17/Treg, obviously reduced proportion of Th2 cells and Treg cells, and evidently elevated levels of Gd-IgA1, BAFF, and their cytokines (IL-4, IL-6, and IL-17) in the peripheral blood. (3) Following 48 weeks of follow-up after intervention treatment with YYHF, the levels of Gd-IgA1, BAFF, IL-6, and IL-17 were significantly lower, but the level of IL-4 was higher in peripheral blood of patients with IgAN than those before treatment and after 24 weeks of treatment; simultaneously, the proportion of Th1 cells, Th17 cells, Th1/Th2, Th1/Treg, Th2/Treg, and Th17/Treg decreased while that of Th2 cells and Treg cells increased after 48 weeks of follow-up compared with that before treatment in peripheral blood of patients with IgAN. (4) The results of correlation analysis revealed that the level of Gd-IgA1 in peripheral blood of patients with IgAN was positively correlated with the level of BAFF, as well as the proportion of Th1 cells, Th17 cells, Th1/Th2, IL-6, and IL-17 levels, and negatively correlated with the proportion of Treg cells. In addition, the level of Gd-IgA1 in peripheral blood was positively correlated with proteinuria, yet without correlation with hematuria. Conclusion: YYHF can reduce the quantitative level of 24 h urinary protein and urinary red blood cell count in patients with IgAN. Patients with IgAN have obvious T cell immune imbalance. YYHF can significantly reduce the level of Gd-IgA1 in patients with IgAN, and its mechanism may be explained by the reduced level of BAFF in peripheral blood and improved immune balance of T cells.


Assuntos
Medicamentos de Ervas Chinesas , Glomerulonefrite por IGA , Humanos , Citocinas , Galactose , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/diagnóstico , Hematúria , Imunoglobulina A , Interleucina-17 , Interleucina-4 , Interleucina-6 , Medicamentos de Ervas Chinesas/uso terapêutico
13.
Sci Rep ; 13(1): 1152, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36670145

RESUMO

The purpose of this study was to identify the inflammatory cytokines that were associated with pachychoroid neovasculopathy (PNV). Seventy-five eyes of 75 patients with PNV, 145 eyes of 145 patients with neovascular age-related macular degeneration without pachyvessels, and 150 eyes of 150 normal subjects were examined for the levels of intraocular cytokines. In eyes with PNV, the levels of IL-1α, IL-1ß, IL-2, IL-4, IL-10, and VEGF were significantly higher than that of the controls. Logistic regression analysis showed that the highest association with the pachyvessels was found for IL-4, IL-2, and IL-1α. In eyes with PNV, the levels of IL-4, IL-2, IL-5, IL-13, IL-1α, and IL-1ß were significantly higher in eyes with both increased choroidal thickness and choroidal vessel diameter. The strongest correlation with the choroidal thickness and vessel diameter was observed for IL-4. In PNV eyes with polypoidal lesions, the levels of IL-4, IL-17, and TNFß were significantly correlated with the number of polypoidal lesions. Of these cytokines, IL-4 was especially associated with the thickness of the choroidal vessels and the formation of polypoidal lesions. We conclude that IL-4 is most likely involved in establishing the clinical characteristics of PNV and polypoidal vascular remodeling.


Assuntos
Neovascularização de Coroide , Interleucina-4 , Humanos , Neovascularização de Coroide/patologia , Interleucina-2 , Tomografia de Coerência Óptica , Corioide/irrigação sanguínea , Citocinas , Estudos Retrospectivos , Angiofluoresceinografia
14.
PLoS Negl Trop Dis ; 17(1): e0011061, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36716305

RESUMO

BACKGROUND: Few data exist on the distinct cytokine profiles of individuals with malaria coinfections and other diseases. This study focuses on data collation of distinct cytokine profiles between individuals with malaria coinfections and monoinfections to provide evidence for further diagnostic or prognostic studies. METHODS: We searched five medical databases, including Embase, MEDLINE, PubMed, Ovid, and Scopus, for articles on cytokines in malaria coinfections published from January 1, 1983 to May 3, 2022, after which the distinct cytokine patterns between malaria coinfection and monoinfection were illustrated in heat maps. RESULTS: Preliminary searches identified 2127 articles, of which 34 were included in the systematic review. Distinct cytokine profiles in malaria coinfections with bacteremia; HIV; HBV; dengue; filariasis; intestinal parasites; and schistosomiasis were tumor necrosis factor (TNF), interferon (IFN)-γ, IFN-α, interleukin (IL)-1, IL-1 receptor antagonist (Ra), IL-4, IL-7, IL-12, IL-15, IL-17; TNF, IL-1Ra, IL-4, IL-10, IL-12, IL-18, CCL3, CCL5, CXCL8, CXCL9, CXCL11, granulocyte colony-stimulating factor (G-CSF); TNF, IFN-γ, IL-4, IL-6, IL-10, IL-12, CCL2; IFN-γ, IL-1, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, CCL2, CCL3, CCL4, G-CSF; IL-1Ra, IL-10, CXCL5, CXCL8, CXCL10; TNF, IL-2, IL-4, IL-6, IL-10; and TNF, IFN-γ, IL-4, IL-5, IL-10, transforming growth factor-ß, CXCL8, respectively. CONCLUSION: This systematic review provides information on distinct cytokine profiles of malaria coinfections and malaria monoinfections. Further studies should investigate whether specific cytokines for each coinfection type could serve as essential diagnostic or prognostic biomarkers for malaria coinfections.


Assuntos
Coinfecção , Malária , Humanos , Interleucina-10 , Interleucina-17 , Interleucina-6 , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-4 , Citocinas , Interleucina-12 , Fator de Necrose Tumoral alfa , Interferon gama , Fator Estimulador de Colônias de Granulócitos , Malária/complicações
15.
Immun Inflamm Dis ; 11(1): e768, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36705412

RESUMO

OBJECTIVE: Helicobacter pylori is planted in the human stomach and is the most common cause of chronic gastritis, which produced specific local and systemic humoral immunity, while the associations of these immune responses and H. pylori in the development of chronic gastritis remain unclear. METHODS: This study analyzed histology, the number of Th22 and regulatory T (Treg) cells, and the levels of inflammation- and gastritis-related indicators between 22 H. pylori-infected and 24 non-H. pylori-infected chronic gastritis patients by hematoxylin-eosin staining, enzyme-linked immunosorbent assay, quantitative reverse transcription PCR, and flow cytometry analysis. RESULTS: This study found that the pathological damage degree of gastric mucosa in H. pylori infection patients was more serious. In the H. pylori-infected patient serum, the gastrin, G-17, interleukins (IL)-22, transforming growth factor (TGF)-ß, tumor necrosis factor (TNF)-α, IL-4, and IL-17A levels were notably raised, while the interferon (IFN)-γ level was inhibited, and in gastric mucosa, and except IFN-γ, the IL-22, forkhead box P3 (Foxp3), TNF-α, IL-4, and IL-17A mRNA levels were raised too. The receiver operating characteristic curve analysis indicates serum IL-22, TGF-ß, TNF-α, IL-4, and IL-17A are suitable for differential diagnosis of H. pylori infection. In addition, in the peripheral blood, the percentages of the IL-22+ CD4+ and Foxp3+ CD4+ T cells were raised with H. pylori infection. The positive correlation between IL-22 and Foxp3 mRNA levels and the degree of H. pylori colonization and gastric mucositis by Pearson's correlation analysis. CONCLUSIONS: Treg and Th22 cells were positively associated with the degree of H. pylori infection and the severity of gastritis. In summary, this study provides an experimental basis for the study of the eradication of H. pylori and the biological mechanism of chronic gastritis.


Assuntos
Gastrite , Infecções por Helicobacter , Helicobacter pylori , Humanos , Linfócitos T Reguladores , Interleucina-17/metabolismo , Helicobacter pylori/genética , Fator de Necrose Tumoral alfa/metabolismo , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/patologia , Interleucina-4 , Gastrite/metabolismo , Gastrite/patologia , Fator de Crescimento Transformador beta/metabolismo , Interferon gama/metabolismo , RNA Mensageiro/metabolismo , Fatores de Transcrição Forkhead/genética
16.
FASEB J ; 37(2): e22761, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36629780

RESUMO

Fibrosis of the skin and internal organs is a hallmark of systemic sclerosis (SSc). Although the pathogenesis of SSc is poorly understood, increasing evidence suggests that interleukins (IL)-4 and - 13 contribute to the pathogenesis of skin fibrosis by promoting collagen production and myofibroblast differentiation. Signal transducers and activators of transcription 6 (STAT6) is one of the most important downstream transcription factors activated by both IL-4 and IL-13. However, it is not completely understood whether STAT6 plays a role during the pathogenesis of skin fibrosis in SSc. In this study, we observed increased STAT6 phosphorylation in fibrotic skin samples collected from SSc patients as well as bleomycin-injected murine mice. Knockout of Stat6 in mice significantly (1) suppressed the expression of fibrotic cytokines including Il13, Il17, Il22, Ccl2, and the alternatively activated macrophage marker Cd206; (2) reduced the production of collagen and fibronectin, and (3) attenuated late-stage skin fibrosis and inflammation induced by bleomycin. Consistently, mice treated with STAT6 inhibitor AS1517499 also attenuated skin fibrosis on day 28. In addition, a co-culture experiment demonstrated that skin epithelial cells with STAT6 knockdown had reduced cytokine expression in response to IL-4/IL-13, and subsequently attenuated fibrotic protein expression in skin fibroblasts. On the other side, STAT6 depletion in skin fibroblasts attenuated IL-4/IL-13-induced cytokine and fibrotic marker expression, and reduced CXCL2 expression in co-cultured keratinocytes. In summary, our study highlighted an important yet not fully understood role of STAT6 in skin fibrosis by driving innate inflammation and differentiation of alternatively activated macrophages in response to injury.


Assuntos
Bleomicina , Escleroderma Sistêmico , Animais , Camundongos , Bleomicina/toxicidade , Interleucina-4/genética , Interleucina-4/metabolismo , Interleucina-13/genética , Interleucina-13/metabolismo , Camundongos Knockout , Fibrose , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo , Colágeno/metabolismo , Fibroblastos/metabolismo , Inflamação/metabolismo , Pele/metabolismo , Modelos Animais de Doenças , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/metabolismo
17.
Genes (Basel) ; 14(1)2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36672948

RESUMO

BACKGROUND: Tuberculosis (TB) manifests itself primarily in the lungs as pulmonary disease (PTB) and sometimes disseminates to other organs to cause extra-pulmonary TB, such as lymph node TB (LNTB). This study aimed to investigate the role of host genetic polymorphism in immunity related genes to find a genetic basis for such differences. METHODS: Sixty-three, Single nucleotide polymorphisms (SNPs) in twenty-three, TB-immunity related genes including eleven innate immunity (SLCA11, VDR, TLR2, TLR4, TLR8, IRGM, P2RX7, LTA4H, SP110, DCSIGN and NOS2A) and twelve cytokine (TNFA, IFNG, IL2, Il12, IL18, IL1B, IL10, IL6, IL4, rs1794068, IL8 and TNFB) genes were investigated to find genetic associations in both PTB and LNTB as compared to healthy community controls. The serum cytokine levels were correlated for association with the genotypes. RESULTS: PTB and LNTB showed differential genetic associations. The genetic variants in the cytokine genes (IFNG, IL12, IL4, TNFB and IL1RA and TLR2, 4 associated with PTB susceptibility and cytokine levels but not LNTB (p < 0.05). Similarly, genetic variants in LTA4H, P2RX7, DCSIGN and SP110 showed susceptibility to LNTB and not PTB. Pathway analysis showed abundance of cytokine related variants for PTB and apoptosis related variants for LNTB. CONCLUSIONS: PTB and LNTB outcomes of TB infection have a genetic component and should be considered for any future functional studies or studies on susceptibility to pulmonary and extra-pulmonary TB.


Assuntos
Tuberculose dos Linfonodos , Tuberculose Pulmonar , Humanos , Predisposição Genética para Doença , Tuberculose Pulmonar/genética , Receptor 2 Toll-Like/genética , Interleucina-4/genética , Citocinas/genética , Polimorfismo de Nucleotídeo Único , Interleucina-12/genética , Pulmão
18.
Vet Res ; 54(1): 2, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627694

RESUMO

The expression of proinflammatory (IL-1ß, IFN-γ, TNF-α) and regulatory (IL-10, TGF-ß, IL-4) cytokines, as well as the transcription factor FoxP3, was quantified in the liver and hepatic lymph node (HLN) of sheep primoinfected and reinfected with Fasciola hepatica at early (4, 8 and 16 days post-infection [dpi]) and late (100 dpi) stages. The liver exerted a Th2 immune response at very early stages after the primoinfection with F. hepatica that induced the downregulation of IFN-γ, followed by a Th1/Th2/Treg response although the late stages were characterised by the expression of Th1/Th2 immune mediators. Contrarily, in reinfected sheep a robust mixed Th1/Th2/Treg immune response was found at very early stages meanwhile at late stages we observed a Th2/Treg immune response overcoming the expression of Th1 immune mediators. However, the HLN displayed a completely different Th1/Th2/Treg expression profile compared to the liver. Primoinfections with F. hepatica in HLN induced a mixed Th1/Th2/Treg environment from early stages, establishing a Th2 immune response at a late stage. However, the reinfected sheep exerted a Th2 immune response at early stages led by the IL-4 expression in opposition to the Th1/Th2/Treg found in the liver, meanwhile at late stages the HLN of reinfected sheep exerted a mixed Th1/Th2/Treg immune response. This is the first work publishing the expression of immune mediators in the liver and HLN from reinfected sheep with F. hepatica. The study of the immune responses exerted by the natural host in the target organs directly implied in the development of F. hepatica are crucial to better understand the immunopathogenesis of the fasciolosis being a key factor to develop effective vaccines.


Assuntos
Fasciola hepatica , Fasciolíase , Doenças dos Ovinos , Ovinos , Animais , Fasciola hepatica/fisiologia , Interleucina-4 , Reinfecção/patologia , Reinfecção/veterinária , Linfócitos T Reguladores , Fasciolíase/veterinária , Fígado/patologia , Fatores de Transcrição , Imunidade , Linfonodos , Doenças dos Ovinos/patologia
19.
BMC Complement Med Ther ; 23(1): 11, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647064

RESUMO

PURPOSE: Ulcerative Colitis (UC) is a chronic nonspecific inflammatory disease of the colon and rectum. Fructus Mume (FM) and Rhizoma Coptidis (RC) exert effects on inflammatory and immune diseases. We evaluated the hypothesis of the FM and RC (FM-RC) herb pair remedy in alleviating dextran sulfate sodium (DSS)-induced colitis, through network pharmacology-based analyses, molecular docking, and experimental validation. METHODS: The Traditional Chinese medicine systematic pharmacology analysis platform(TCMSP) and Swiss database were used to predict potential targets of FM-RC and the GeneCards database was utilized to collect UC genes. Cytoscape software was used to construct and analyze the networks, and DAVID was utilized to perform enrichment analysis. AutoDock software was used to dock the core chemical components of the FM-RC herb pair with key UC targets. Animal experiments were performed to validate the prediction results and general conditions and body weight were observed. Pathological changes in colon tissue were observed by staining with hematoxylin and eosin. The levels of TNF-α, IL-8, IL-17, and IL-4 in serum and colon tissue were detected by ELISA. RESULTS: Eighteen effective components of the herb couple were screened, and their potential therapeutic targets in the treatment of UC were acquired from 110 overlapped targets. GO and KEGG analyses revealed that these targets were highly correlated with protein autophosphorylation, plasma membrane, ATP binding, cancer pathways, the PI3K-AKt signaling pathway, and the Rap1 signaling pathway. Molecular docking established the core protein interactions with compounds having a docking energy < 0 kJ·mol-1, indicating the core active components had strong binding activities with the core targets. FM-RC herb pair relieved pathological indicators and reduced the concentration of TNF-α, IL-8, and IL-17 and increased IL-4 levels in the serum and colon tissues of UC rats. CONCLUSION: Collectively, FM-RC herb pair administration alleviated UC. These beneficial effects targeted MAPK1 signaling related to inflammation and immunity, which provided a basis for a better understanding of FM-RC in the treatment of UC.


Assuntos
Antineoplásicos , Colite Ulcerativa , Medicamentos de Ervas Chinesas , Ratos , Animais , Colite Ulcerativa/genética , Simulação de Acoplamento Molecular , Interleucina-17/efeitos adversos , Medicamentos de Ervas Chinesas/química , Fator de Necrose Tumoral alfa , Interleucina-4 , Interleucina-8 , Fosfatidilinositol 3-Quinases , Inflamação/tratamento farmacológico , Antineoplásicos/uso terapêutico
20.
ACS Appl Mater Interfaces ; 15(2): 2590-2601, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36607242

RESUMO

Barrier membranes for guided tissue regeneration are essential for bone repair and regeneration. The implanted membranes may trigger early inflammatory responses as a foreign material, which can affect the recruitment and differentiation of bone cells during tissue regeneration. The purpose of this study was to determine whether immobilizing interleukin 4 (IL4) on plasma immersion ion implantation (PIII)-activated surfaces may alter the osteo-immunoregulatory characteristics of the membranes and produce pro-osteogenic effects. In order to immobilize IL4, polycaprolactone surfaces were modified using the PIII technology. No discernible alterations were found between the morphology before and after PIII treatment or IL4 immobilization. IL4-immobilized PIII surfaces polarized macrophages to an M2 phenotype and mitigated inflammatory cytokine production under lipopolysaccharide stimulation. Interestingly, the co-culture of macrophages (on IL4-immobilized PIII surfaces) and bone marrow-derived mesenchymal stromal cells enhanced the production of angiogenic and osteogenic factors and triggered autophagy activation. Exosomes produced by PIII + IL4-stimulated macrophages were also found to play a role in osteoblast differentiation. In conclusion, the osteo-immunoregulatory properties of bone materials can be modified by PIII-assisted IL4 immobilization, creating a favorable osteoimmune milieu for bone regeneration.


Assuntos
Imersão , Interleucina-4 , Osteogênese/fisiologia , Osso e Ossos , Regeneração Óssea
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