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Fulltext Contribution of IL-33/ILC2-mediated Th2 cytokines during the progression of minimal change disease

Liu C, Liu L, Huang Y, Shi R, Wu Y, Hakimah Binti Ismail I

Int Immunopharmacol, 2023 Jan;114:109493.
PMID: 36527879 DOI: 10.1016/j.intimp.2022.109493

Minimal change disease (MCD) is a common type of nephrotic syndrome with high recurrence rate. This study aims to explore the impacts of interleukin (IL)-33 in MCD and to discuss its potential mechanism. In adriamycin (ADM) and puromycin aminonucleoside (PAN)-induced MCD rat model, IL-33 was used for treatment. H&E staining was applied for detecting histological changes. Critical proteins were examined by western blot. Corresponding commercial kits tested oxidative stress- and inflammation-related factors. Cell apoptosis was measured by TUNEL assay. ADM-induced podocyte injury model was establish to mimic MCD in vitro. Cell proliferation and apoptosis were detected by CCK-8 and TUNEL assays. Finally, podocyte was stimulated by innate lymphoid type-2 cells-secreted Th2 cytokines (ILC2s: IL-13 and IL-5 respectively), with or without incubation with M1 macrophage medium to further explore the immune-regulation of ILC2s behind the inflammatory environment of MCD. It was found that PAN-induced kidney jury, inflammation, oxidative stress and apoptosis were severer than ADM, and IL-33 treatment significantly alleviated the above injuries in PAN and ADM-induced MCD rat model. Moreover, IL-33 reversed the reduced viability and increased oxidative stress and apoptosis in ADM-induced podocyte injury model. Further, the capacities of IL-13 alone in inducing M1/M2 macrophage polarization, apoptosis, inflammation, kidney injury and reducing cell viability are stronger than IL-5. However, IL-13 reversed reduced cell viability and stimulated apoptosis, inflammation, kidney injury mediated by co-incubation with M1-conditioned medium. Collectively, IL-33 might protect against immunologic injury in MCD via mediating ILC2s-secreted IL-13.

Matched MeSH terms: Interleukin-5
Fulltext Cytokine expression profile of dengue patients at different phases of illness

Rathakrishnan A, Wang SM, Hu Y, Khan AM, Ponnampalavanar S, Lum LC, et al.

PLoS One, 2012;7(12):e52215.
PMID: 23284941 DOI: 10.1371/journal.pone.0052215

BACKGROUND: Dengue is an important medical problem, with symptoms ranging from mild dengue fever to severe forms of the disease, where vascular leakage leads to hypovolemic shock. Cytokines have been implicated to play a role in the progression of severe dengue disease; however, their profile in dengue patients and the synergy that leads to continued plasma leakage is not clearly understood. Herein, we investigated the cytokine kinetics and profiles of dengue patients at different phases of illness to further understand the role of cytokines in dengue disease.
METHODS AND FINDINGS: Circulating levels of 29 different types of cytokines were assessed by bead-based ELISA method in dengue patients at the 3 different phases of illness. The association between significant changes in the levels of cytokines and clinical parameters were analyzed. At the febrile phase, IP-10 was significant in dengue patients with and without warning signs. However, MIP-1β was found to be significant in only patients with warning signs at this phase. IP-10 was also significant in both with and without warning signs patients during defervescence. At this phase, MIP-1β and G-CSF were significant in patients without warning signs, whereas MCP-1 was noted to be elevated significantly in patients with warning signs. Significant correlations between the levels of VEGF, RANTES, IL-7, IL-12, PDGF and IL-5 with platelets; VEGF with lymphocytes and neutrophils; G-CSF and IP-10 with atypical lymphocytes and various other cytokines with the liver enzymes were observed in this study.
CONCLUSIONS: The cytokine profile patterns discovered between the different phases of illness indicate an essential role in dengue pathogenesis and with further studies may serve as predictive markers for progression to dengue with warning signs.

Matched MeSH terms: Interleukin-5/blood
Fulltext A Synthetic Curcuminoid Analogue, 2,6-Bis-4-(Hydroxyl-3-Methoxybenzylidine)-Cyclohexanone (BHMC) Ameliorates Acute Airway Inflammation of Allergic Asthma in Ovalbumin-Sensitized Mice

Tham CL, Yeoh SY, Ong CH, Harith HH, Israf DA

Mediators Inflamm, 2021;2021:9725903.
PMID: 33883974 DOI: 10.1155/2021/9725903

2,6-Bis-(4-hydroxyl-3-methoxybenzylidine) cyclohexanone (BHMC), a synthetic curcuminoid analogue, has been shown to exhibit anti-inflammatory properties in cellular models of inflammation and improve the survival of mice from lethal sepsis. We further evaluated the therapeutic effect of BHMC on acute airway inflammation in a mouse model of allergic asthma. Mice were sensitized and challenged with ovalbumin (OVA), followed by intraperitoneal administration of 0.1, 1, and 10 mg/kg of BHMC. Bronchoalveolar lavage fluid, blood, and lung samples were collected, and the respiratory function was measured. OVA sensitization and challenge increased airway hyperresponsiveness (AHR) and pulmonary inflammation. All three doses of BHMC (0.1-10 mg/kg) significantly reduced the number of eosinophils, lymphocytes, macrophages, and neutrophils, as well as the levels of Th2 cytokines (IL-4, IL-5 and IL-13) in bronchoalveolar lavage fluid (BALF) as compared to OVA-challenged mice. However, serum level of IgE was not affected. All three doses of BHMC (0.1-10 mg/kg) were effective in suppressing the infiltration of inflammatory cells at the peribronchial and perivascular regions, with the greatest effect observed at 1 mg/kg which was comparable to dexamethasone. Goblet cell hyperplasia was inhibited by 1 and 10 mg/kg of BHMC, while the lowest dose (0.1 mg/kg) had no significant inhibitory effect. These findings demonstrate that BHMC, a synthetic nonsteroidal small molecule, ameliorates acute airway inflammation associated with allergic asthma, primarily by suppressing the release of inflammatory mediators and goblet cell hyperplasia to a lesser extent in acute airway inflammation of allergic asthma.

Matched MeSH terms: Interleukin-5
Fulltext In silico-guided sequence modifications of K-ras epitopes improve immunological outcome against G12V and G13D mutant KRAS antigens

Ng AWR, Tan PJ, Hoo WPY, Liew DS, Teo MYM, Siak PY, et al.

PeerJ, 2018;6:e5056.
PMID: 30042874 DOI: 10.7717/peerj.5056

Background: Somatic point substitution mutations in the KRAS proto-oncogene primarily affect codons 12/13 where glycine is converted into other amino acids, and are highly prevalent in pancreatic, colorectal, and non-small cell lung cancers. These cohorts are non-responsive to anti-EGFR treatments, and are left with non-specific chemotherapy regimens as their sole treatment options. In the past, the development of peptide vaccines for cancer treatment was reported to have poor AT properties when inducing immune responses. Utilization of bioinformatics tools have since become an interesting approach in improving the design of peptide vaccines based on T- and B-cell epitope predictions.
Methods: In this study, the region spanning exon 2 from the 4th to 18th codon within the peptide sequence of wtKRAS was chosen for sequence manipulation. Mutated G12V and G13D K-ras controls were generated in silico, along with additional single amino acid substitutions flanking the original codon 12/13 mutations. IEDB was used for assessing human and mouse MHC class I/II epitope predictions, as well as linear B-cell epitopes predictions, while RNA secondary structure prediction was performed via CENTROIDFOLD. A scoring and ranking system was established in order to shortlist top mimotopes whereby normalized and reducing weighted scores were assigned to peptide sequences based on seven immunological parameters. Among the top 20 ranked peptide sequences, peptides of three mimotopes were synthesized and subjected to in vitro and in vivo immunoassays. Mice PBMCs were treated in vitro and subjected to cytokine assessment using CBA assay. Thereafter, mice were immunized and sera were subjected to IgG-based ELISA.
Results: In silico immunogenicity prediction using IEDB tools shortlisted one G12V mimotope (68-V) and two G13D mimotopes (164-D, 224-D) from a total of 1,680 candidates. Shortlisted mimotopes were predicted to promote high MHC-II and -I affinities with optimized B-cell epitopes. CBA assay indicated that: 224-D induced secretions of IL-4, IL-5, IL-10, IL-12p70, and IL-21; 164-D triggered IL-10 and TNF-α; while 68-V showed no immunological responses. Specific-IgG sera titers against mutated K-ras antigens from 164-D immunized Balb/c mice were also elevated post first and second boosters compared to wild-type and G12/G13 controls.
Discussion: In silico-guided predictions of mutated K-ras T- and B-cell epitopes were successful in identifying two immunogens with high predictive scores, Th-bias cytokine induction and IgG-specific stimulation. Developments of such immunogens are potentially useful for future immunotherapeutic and diagnostic applications against KRAS(+) malignancies, monoclonal antibody production, and various other research and development initiatives.

Matched MeSH terms: Interleukin-5
Fulltext Deciphering the Association of Cytokines, Chemokines, and Growth Factors in Chondrogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells Using an ex vivo Osteochondral Culture System

Jafri MA, Kalamegam G, Abbas M, Al-Kaff M, Ahmed F, Bakhashab S, et al.

Front Cell Dev Biol, 2019;7:380.
PMID: 32010693 DOI: 10.3389/fcell.2019.00380

Osteoarthritis (OA) is a chronic degenerative joint disorder associated with degradation and decreased production of the extracellular matrix, eventually leading to cartilage destruction. Limited chondrocyte turnover, structural damage, and prevailing inflammatory milieu prevent efficient cartilage repair and restoration of joint function. In the present study, we evaluated the role of secreted cytokines, chemokines, and growth factors present in the culture supernatant obtained from an ex vivo osteochondral model of cartilage differentiation using cartilage pellets (CP), bone marrow stem cells (BM-MSCs), and/or BM-MSCs + CP. Multiplex cytokine analysis showed differential secretion of growth factors (G-CSF, GM-CSF, HGF, EGF, VEGF); chemokines (MCP-1, MIP1α, MIP1β, RANTES, Eotaxin, IP-10), pro-inflammatory cytokines (IL-1β, IL-2, IL-5, IL-6, IL-8, TNFα, IL-12, IL-15, IL-17) and anti-inflammatory cytokines (IL-4, IL-10, and IL-13) in the experimental groups compared to the control. In silico analyses of the role of stem cells and CP in relation to the expression of various molecules, canonical pathways and hierarchical cluster patterns were deduced using the Ingenuity Pathway Analysis (IPA) software (Qiagen, United States). The interactions of the cytokines, chemokines, and growth factors that are involved in the cartilage differentiation showed that stem cells, when used together with CP, bring about a favorable cell signaling that supports cartilage differentiation and additionally helps to attenuate inflammatory cytokines and further downstream disease-associated pro-inflammatory pathways. Hence, the autologous or allogeneic stem cells and local cartilage tissues may be used for efficient cartilage differentiation and the management of OA.

Matched MeSH terms: Interleukin-5
Fulltext Cytokines secreted by human Wharton's jelly stem cells inhibit the proliferation of ovarian cancer (OVCAR3) cells in vitro

Kalamegam G, Sait KHW, Anfinan N, Kadam R, Ahmed F, Rasool M, et al.

Oncol Lett, 2019 May;17(5):4521-4531.
PMID: 30944641 DOI: 10.3892/ol.2019.10094

Cytokines enhance tumour cell recognition via cytotoxic effector cells and are therefore effectively used in cancer immunotherapy. Mesenchymal stem cells have efficient homing potential and have been used to target and inhibit various types of cancer mediated by the release of soluble/bioactive factors. Initial evaluation of the human Wharton's jelly stem cell conditioned medium (hWJSC-CM) and cell lysate (hWJSC-CL) against an ovarian cancer cell line (OVCAR3) demonstrated their inhibitory effect in vitro. The secreted cytokine profile was then studied to understand whether the OVCAR3 inhibitory effect was mediated by the cytokines. Expression of cytokines in OVCAR3 following 48 h treatment with hWJSC extracts, namely the hWJSC-CM (50%) and hWJSC-CL (10 µg/ml), was evaluated using multiplex cytokine assay. Paclitaxel (5 nM) was used as a positive control. Cytokines tumour necrosis factor α, interleukin (IL)-4, IL-6, IL-8, IL-10, IL-13, IL-17, IL-1β and granulocyte colony-stimulating factor, reported to be involved in tumour growth, invasion and migration, were significantly decreased. Cytokines with antitumour effects, namely IL-1 receptor antagonist (IL-1RA), IL-2, IL-2 receptor, IL-5, IL-7, IL-12, IL-15, interferon (IFN)-α and IFN-γ, were mildly increased or decreased. Only the increases in IL-1RA (with paclitaxel, hWJSC-CM and hWJSC-CL) and granulocyte-macrophage colony-stimulating factor (with hWJSC-CL) were statistically significant. The chemokines monocyte chemoattractant protein 1, macrophage inflammatory protein (MIP)-1α, MIP-1β and Regulated Upon Activation, Normally T-Expressed, and Secreted were significantly decreased while monokine induced by IFN-γ, IFN-γ induced protein 10 and Eotaxin demonstrated mild decreases. The growth factors basic fibroblast growth factor, vascular endothelial growth factor and hepatocyte growth factor were significantly decreased. Heatmaps demonstrated differential fold changes in cytokines and hierarchical cluster analysis revealed 3 major and 7 minor sub-clusters of associated cytokines, chemokines and growth factors. In conclusion, the hWJSC extracts decreased the expression of oncogenic cytokines, chemokines and growth factors, which mediated the inhibition of OVCAR3 cells in vitro.

Matched MeSH terms: Interleukin-5
Fulltext HLA-DRB1*04 as a Risk Allele to Systemic Lupus Erythematosus and Lupus Nephritis in the Malay Population of Malaysia

Selvaraja M, Chin VK, Abdullah M, Arip M, Amin-Nordin S

Front Med (Lausanne), 2020;7:598665.
PMID: 33644084 DOI: 10.3389/fmed.2020.598665

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease afflicting multiple organs. Lupus nephritis (LN) is a serious complication of SLE and remains a major cause of mortality and morbidity. Curative therapy remains unavailable as etiology from genetic and environmental factors is still unclear. The present study was conducted to elucidate the link between HLA-DRB1 gene polymorphisms with SLE and LN through clinical and laboratory/biological presentations in a population of Malaysian Malay females with SLE. A total of 100 Malay female SLE patients inclusive of 70 SLE patients without LN and 30 patients with LN were included in this study. HLA-DRB1 allele examination in SLE patients was performed using PCR-SSO, and the alleles' frequencies were compared with 951 publicly available datasets representing Malay healthy controls in Malaysia. Cytokines and free radical levels were detected by ELISA and bead-based multiplexed Luminex assays. The association between HLA-DRB1 alleles with clinical and serological manifestations and immune mediators was analyzed using different statistical approaches whenever applicable. Our study showed that HLA-DRB1*0405, HLA-DRB1*1502, and HLA-DRB1*1602 were associated with the increased risk of SLE while HLA-DRB1*1201 and HLADRB1*1202 alleles were associated with a lower risk of SLE development. Furthermore, HLA-DRB1*04 showed significant association to LN and arthritis while HLA-DRB1*15 was significantly associated with oral ulcer in Malay SLE patients. Association analysis of HLA-DRB1*04 with clinical and biological factors revealed that HLA-DRB1*04 was significantly associated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, anti-nuclear antibody (ANA), C-reactive protein (CRP) in the blood, and total protein in the urine. SLE carriers with the HLA-DRB1*04 allele were significantly correlated to the increased levels of cytokines (IFN-y, GM-CSF, IL-17F, IL-18, IL-21, and VEGF) and were significantly showing negative correlation to IL-5 and free radicals (LPO and catalase enzyme) levels compared to SLE carriers without HLA-DRB1*04 allele. The results suggested that disease severity in SLE may be determined by HLA-DRB1 alleles. The risk of HLA-DRB1*04 allele with LN was supported by the demonstration of an intense inflammatory response in Malay SLE patients in Malaysia. More studies inclusive of a larger and multiple SLE cohorts in the future are warranted to validate these findings.

Matched MeSH terms: Interleukin-5