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Fulltext Tropomyosin Receptor Kinase C Targeted Delivery of a Peptidomimetic Ligand-Photosensitizer Conjugate Induces Antitumor Immune Responses Following Photodynamic Therapy

Kue CS, Kamkaew A, Voon SH, Kiew LV, Chung LY, Burgess K, et al.

Sci Rep, 2016 11 17;6:37209.
PMID: 27853305 DOI: 10.1038/srep37209

Tropomyosin receptor kinase C (TrkC) targeted ligand-photosensitizer construct, IYIY-diiodo-boron-dipyrromethene (IYIY-I2-BODIPY) and its scrambled counterpart YIYI-I2-BODIPY have been prepared. IYIY-I2-BODIPY binds TrkC similar to neurotrophin-3 (NT-3), and NT-3 has been reported to modulate immune responses. Moreover, it could be shown that photodynamic therapy (PDT) elevates antitumor immune responses. This prompted us to investigate the immunological impacts mediated by IYIY-I2-BODIPY in pre- and post-PDT conditions. We demonstrated that IYIY-I2-BODIPY (strong response) and YIYI-I2-BODIPY (weak response) at 10 mg/kg, but not I2-BODIPY control, increased the levels of IL-2, IL-4, IL-6 and IL-17, but decreased the levels of systemic immunoregulatory mediators TGF-β, myeloid-derived suppressor cells and regulatory T-cells. Only IYIY-I2-BODIPY enhanced the IFN-γ+ and IL-17+ T-lymphocytes, and delayed tumor growth (~20% smaller size) in mice when administrated daily for 5 days. All those effects were observed without irradiation; when irradiated (520 nm, 100 J/cm2, 160 mW/cm2) to produce PDT effects (drug-light interval 1 h), IYIY-I2-BODIPY induced stronger responses. Moreover, photoirradiated IYIY-I2-BODIPY treated mice had high levels of effector T-cells compared to controls. Adoptive transfer of immune cells from IYIY-I2-BODIPY-treated survivor mice that were photoirradiated gave significantly delayed tumor growth (~40-50% smaller size) in recipient mice. IYIY-I2-BODIPY alone and in combination with PDT modulates the immune response in such a way that tumor growth is suppressed. Unlike immunosuppressive conventional chemotherapy, IYIY-I2-BODIPY can act as an immune-stimulatory chemotherapeutic agent with potential applications in clinical cancer treatment.

Matched MeSH terms: Th17 Cells/immunology*; Th17 Cells/pathology
Evaluation of Th17 associated antigen in Old World Cutaneous Leishmaniasis: A comparative study in acute versus chronic human cutaneous Leishmaniasis using immunohistochemistry

Mortazavi H, Kamyab-Hesari K, Karimi S, Rafati S, Mohebali M, Khamesipour A, et al.

Trop Biomed, 2019 Dec 01;36(4):1061-1070.
PMID: 33597475

There are little information about Th17 cells and cutaneous Leishmaniasis (CL), due to an important effect of Th17 cells on immune response, it is worth to explore the role of Th17 on CL. The purpose of this study was to assess Th17 population in patients with acute vs. chronic CL lesions in comparison with skin samples collected from healthy volunteers in an endemic region of Old World CL. A total of 49 patients with clinical manifestations of chronic (n=16) and acute (n=33) CL lesions were recruited. The clinical diagnosis of CL was confirmed by direct smear or PCR. Biopsy specimens from prelesional skin of non-infectious lesions of 30 healthy individuals were used as control. Tissue sections of 3µm thickness were prepared and used for immunohistochemistry (IHC) analysis with primary antibody specific for Th17 associated antigen (CD161). For IHC, Envision+ (DakoCytomation) system was used and developed by using diaminobenzidine (DakoCytomation). The mean age of 33 patients with acute CL and the mean age of 16 patients with chronic CL were accordingly 45.24±16.43 and 33.56±15.87. In acute and chronic CL the mean (±standard deviation) and median (±interquartile range) were accordingly 2.92±2.21, 2.56±2.9 and 2.1±1.99, 1.54±2.81. In healthy controls the mean (±standard deviation) and median (±interquartile range) were 0.72±0.41 and 0.61±0.58 respectively. With pairwise comparison of acute, chronic and control groups, there were significant difference between acute and control (P value < 0.001), chronic and control (P value = 0.043). The results showed that there was an increasing cellular response of Th17 in both acute and chronic CL patients. Th17 was significantly higher in patients with acute and chronic CL lesions in comparison with healthy control group. However, there was no significant difference between acute and chronic infection concerning to Th17 cells.

Matched MeSH terms: Th17 Cells/immunology*
Association between polymorphisms of interleukin-17A G197A and interleukin-17F A7488G and risk of colorectal cancer

Samiei G, Yip WK, Leong PP, Jabar MF, Dusa NM, Mohtarrudin N, et al.

J Cancer Res Ther, 2018 Jun;14(Supplement):S299-S305.
PMID: 29970680 DOI: 10.4103/0973-1482.235345

Background: Interleukin (IL)-17A and IL-17F are inflammatory cytokines mainly produced by T helper 17 cells. IL-17A is known to be protumorigenic while IL-17F has a protective role in cancer. A number of studies have been conducted to determine the association between polymorphisms of IL-17AG197A (rs2275913) and IL-17FA7488G (rs763780) and risk of cancers. No studies have yet to be conducted to genotype the IL-17AG197A polymorphism in colorectal cancer (CRC).
Objective: To assess the association of IL-17AG197A and IL-17FA7488G polymorphisms with CRC risk.
Materials and Methods: We performed the genotyping by polymerase chain reaction-restriction fragment length polymorphism method on blood samples from 80 healthy individuals and paraffin-embedded tumor tissues from 70 CRC patients.
Results: Our study showed that IL-17A197AA genotype was significantly associated with an increased CRC risk with odds ratios of 6.08 (95% confidence interval [CI]: 2.25-16.42, P < 0.001) and 2.80 (95% CI: 1.23-6.35, P = 0.014), in comparison with GG and AG genotypes, respectively. However, IL-17FA7488G polymorphism was not significantly associated with CRC risk (P = 0.102). No significant association of IL-17AG197A and IL-17FA7488G polymorphisms with patient and tumor variables was found.
Conclusion: This report from Malaysia shows the relationship of IL-17A197AA genotype with susceptibility to CRC.

Matched MeSH terms: Th17 Cells
Artesunate attenuates 2, 4-dinitrochlorobenzene-induced atopic dermatitis by down-regulating Th17 cell responses in BALB/c mice

Bai XY, Liu P, Chai YW, Wang Y, Ren SH, Li YY, et al.

Eur J Pharmacol, 2020 May 05;874:173020.
PMID: 32087254 DOI: 10.1016/j.ejphar.2020.173020

Steroidal agent is a standard clinical treatment of atopic dermatitis; however, have serious side effects. Artesunate is reported to exhibit anti-inflammatory properties although its effect on atopic eczema remains unknown. We investigated the therapeutic effects and possible mechanism of systemic artesunate on DNCB-induced atopic dermatitis in a BALB/c mouse model. To ascertain artesunate (5 and 10 mg/kg) efficacy, skin dermatitis severity and ear, spleen, and lymph node weight were evaluated. Skin tissue mRNA and protein expression and serum cytokine levels were examined. Artesunate significantly improved atopic dermatitis symptoms, decreasing the dermatitis score, ear weight difference, spleen weight, and lymph node weight compared with those following DNCB treatment. Artesunate reduced ear and skin epidermal thickness and mast cell infiltration, as determined using hematoxylin-eosin and toluidine blue staining, respectively. The basal level of IgE (287.67 ± 70.41 ng/ml) and TNF-α (19.94 ± 3.98 pg/ml) were Significantly elevated by DNCB (IgE: 1273.23 ± 176.53 ng/ml; TNF-α: 57.53 ± 3.87 pg/ml), while markedly been suppressed in the treatment group (AS-L: IgE: 1100.25 ± 135.32 ng/ml; TNF-α: 38.47 ± 3.26 pg/ml; AS-H: IgE: 459.46 ± 74.75 ng/ml; TNF-α: 24.38 ± 3.85 pg/ml). Among Th17 cell-related factors, DNCB treatment increased mRNA expression of IL-6, IL-17, IL-23, STAT3, and ROR-γt, but reduced TGF-β and SOCS 3; While artesunate reverse these changes. Compared with the model group, artesunate promoted SOCS3 protein and significantly inhibited ROR-γt protein and STAT3 phosphorylation. Thus, artesunate attenuates DNCB-induced atopic dermatitis by inhibiting the release of inflammatory cytokines and downregulating Th17 cell responses in atopic dermatitis mice.

Matched MeSH terms: Th17 Cells/drug effects*; Th17 Cells/immunology
Fulltext N-glycosylation and expression in human tissues of the orphan GPR61 receptor

Kozielewicz P, Alomar H, Yusof S, Grafton G, Cooper AJ, Curnow SJ, et al.

FEBS Open Bio, 2017 12;7(12):1982-1993.
PMID: 29226084 DOI: 10.1002/2211-5463.12339

A number of members of the G protein-coupled receptor class of cell surface receptors are 'orphans' with no known endogenous ligand. One of these orphan receptors is GPR61; there are little data about its expression in human cells and tissues. In this study, we investigated the post-translational modification of GPR61 by N-glycosylation at an identified consensus N-glycosylation site (N12) and the impact of this modification upon the subcellular expression of the protein. The N-glycosylation inhibitor tunicamycin reduced the apparent molecular weight of immunoreactivity associated with myc-tagged GPR61 by 1-2 kDa, which was comparable to the evident molecular weight of the myc-tagged N12S GPR61 mutant with disrupted consensus N-glycosylation site. Analysis of GPR61 expression demonstrated that tunicamycin treatment reduced considerably heterologous expression of GPR61 in the cell membrane despite the N12S GPR61 mutant being readily expressed at the cell surface. These results demonstrate that GPR61 is subject to N-glycosylation but suggest this is not a prerequisite for cell surface expression, although N-glycosylation of other proteins may be important for cell membrane expression of GPR61. Expression of GPR61 protein was demonstrated at the cellular level in human hippocampus and human peripheral blood mononuclear cells. In the latter, there was a significantly higher expression of GPR61 in the Th17 cell subset in comparison with resting CD4+ cells, which may point toward a potential role for the GPR61 receptor in autoimmune diseases. This is the first report that GPR61 protein is subject to post-translational modification and is expressed in immune cell subsets and the hippocampus. These findings will help guide studies to investigate the function of GPR61.

Matched MeSH terms: Th17 Cells
Fulltext Lung-infiltrating T helper 17 cells as the major source of interleukin-17A production during pulmonary Cryptococcus neoformans infection

Movahed E, Cheok YY, Tan GMY, Lee CYQ, Cheong HC, Velayuthan RD, et al.

BMC Immunol, 2018 Nov 08;19(1):32.
PMID: 30409128 DOI: 10.1186/s12865-018-0269-5

BACKGROUND: IL-17A has emerged as a key player in the pathologies of inflammation, autoimmune disease, and immunity to microbes since its discovery two decades ago. In this study, we aim to elucidate the activity of IL-17A in the protection against Cryptococcus neoformans, an opportunistic fungus that causes fatal meningoencephalitis among AIDS patients. For this purpose, we examined if C. neoformans infection triggers IL-17A secretion in vivo using wildtype C57BL/6 mice. In addition, an enhanced green fluorescence protein (EGFP) reporter and a knockout (KO) mouse models were used to track the source of IL-17A secretion and explore the protective function of IL-17A, respectively.
RESULTS: Our findings showed that in vivo model of C. neoformans infection demonstrated induction of abundant IL-17A secretion. By examining the lung bronchoalveolar lavage fluid (BALF), mediastinal lymph node (mLN) and spleen of the IL-17A-EGFP reporter mice, we showed that intranasal inoculation with C. neoformans promoted leukocytes lung infiltration. A large proportion (~ 50%) of the infiltrated CD4+ helper T cell population secreted EGFP, indicating vigorous TH17 activity in the C. neoformans-infected lung. The infection study in IL-17A-KO mice, on the other hand, revealed that absence of IL-17A marginally boosted fungal burden in the lung and accelerated the mouse death.
CONCLUSION: Therefore, our data suggest that IL-17A is released predominantly from TH17 cells in vivo, which plays a supporting role in the protective immunity against C. neoformans infection.

Matched MeSH terms: Th17 Cells
Th17 and Treg cells function in SARS-CoV2 patients compared with healthy controls

Sadeghi A, Tahmasebi S, Mahmood A, Kuznetsova M, Valizadeh H, Taghizadieh A, et al.

J Cell Physiol, 2021 04;236(4):2829-2839.
PMID: 32926425 DOI: 10.1002/jcp.30047

In the course of the coronavirus disease 2019 (COVID-19), raising and reducing the function of Th17 and Treg cells, respectively, elicit hyperinflammation and disease progression. The current study aimed to evaluate the responses of Th17 and Treg cells in COVID-19 patients compared with the control group. Forty COVID-19 intensive care unit (ICU) patients were compared with 40 healthy controls. The frequency of cells, gene expression of related factors, as well as the secretion levels of cytokines, were measured by flow cytometry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay techniques, respectively. The findings revealed a significant increase in the number of Th17 cells, the expression levels of related factors (RAR-related orphan receptor gamma [RORγt], IL-17, and IL-23), and the secretion levels of IL-17 and IL-23 cytokines in COVID-19 patients compared with controls. In contrast, patients had a remarkable reduction in the frequency of Treg cells, the expression levels of correlated factors (Forkhead box protein P3 [FoxP3], transforming growth factor-β [TGF-β], and IL-10), and cytokine secretion levels (TGF-β and IL-10). The ratio of Th17/Treg cells, RORγt/FoxP3, and IL-17/IL-10 had a considerable enhancement in patients compared with the controls and also in dead patients compared with the improved cases. The findings showed that enhanced responses of Th17 cells and decreased responses of Treg cells in 2019-n-CoV patients compared with controls had a strong relationship with hyperinflammation, lung damage, and disease pathogenesis. Also, the high ratio of Th17/Treg cells and their associated factors in COVID-19-dead patients compared with improved cases indicates the critical role of inflammation in the mortality of patients.

Matched MeSH terms: Th17 Cells